Targeted Degradation of CTCF Decouples Local Insulation of Chromosome Domains from Genomic Compartmentalization

Nora, Elphège P.; Goloborodko, Anton; Valton, Anne-Laure; Gibcus, Johan H.; Uebersohn, Alec; Abdennur, Nezar; Dekker, Job; Mirny, Leonid A.; Bruneau, Benoit G.

doi:10.1016/j.cell.2017.05.004

Cited by 1,709Genomics and Chromatin DynamicsChromatin Remodeling and CancerNuclear Structure and Function

Targeted Degradation of CTCF Decouples Local Insulation of Chromosome Domains from Genomic Compartmentalization

Open access

Nora, Elphège P., Goloborodko, Anton, Valton, Anne-Laure, Gibcus, Johan H., Uebersohn, Alec, Abdennur, Nezar, Dekker, Job, Mirny, Leonid A. +1 more·2017·Cell

DOI 10.1016/j.cell.2017.05.004PMC PMC5538188

Published version of a preprint

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Abstract

Summary The molecular mechanisms underlying folding of mammalian chromosomes remain poorly understood. The transcription factor CTCF is a candidate regulator of chromosomal structure. Using the auxin-inducible degron system in mouse embryonic stem cells, we show that CTCF is absolutely and dose-dependently required for looping between CTCF target sites and insulation of topologically associating domains (TADs). Restoring CTCF reinstates proper architecture on altered chromosomes, indicating a powerful instructive function for CTCF in chromatin folding. CTCF remains essential for TAD organization in non-dividing cells. Surprisingly, active and inactive genome compartments remain properly segregated upon CTCF depletion, revealing that compartmentalization of mammalian chromosomes emerges independently of proper insulation of TADs. Further, our data support that CTCF mediates transcriptional insulator function through enhancer-blocking but not as a direct barrier to heterochromatin spreading. Beyond defining the functions of CTCF in chromosome folding these results provide new fundamental insights into the rules governing mammalian genome organization.

AI snapshot

Written from the paper’s full text.

TL;DR

Acute auxin-inducible degradation of CTCF in mouse embryonic stem cells shows that CTCF is required for CTCF-site looping and TAD insulation but not for A/B compartmentalization. The paper separates local TAD insulation from higher-order genome compartmentalization and supports CTCF as an enhancer blocker rather than a direct H3K27me3 barrier.

Key findings

CTCF depletion abolished CTCF-anchored loops and caused loss of insulation at >80% of TAD boundaries; 1000 persistent CTCF-less boundaries (18% of initial boundaries) remained, and restoring CTCF re-established architecture.
A/B compartments remained properly segregated after CTCF depletion, with only a minor reproducible ~10% reduction in compartmentalization strength; contact-frequency scaling with genomic distance did not change.
Insulation defects were dose-dependent: cells with around 15% residual CTCF preserved more insulation than completely depleted cells, helping explain milder RNAi phenotypes that leave 10–15% CTCF.
RNA-seq showed 370 differentially expressed genes at day 1 and 4996 at day 4; >80% of early down-regulated genes had CTCF bound within 1 kb of the TSS, while up-regulated genes were closer to active enhancers and more often separated from them by a TAD boundary. CTCF depletion did not trigger H3K27me3 spreading.

Methods

Endogenous CTCF was tagged at both Ctcf alleles with an auxin-inducible degron (AID) in E14Tg2a mouse embryonic stem cells, with Tir1 expression and 500 µM auxin/IAA for acute, reversible depletion; cells were also differentiated into neural precursor cells and resting astrocytes.
Chromosome conformation was assayed by 5C at the Xic and by Hi-C at 20 kb/100 kb resolution, alongside ChIP-seq, ChIP-exo, RNA-seq time courses, 3D DNA FISH, Western blotting, flow cytometry, and proliferation assays.
Analyses included insulation-score boundary calling, A/B compartment eigenvector analysis, differential expression, CTCF motif orientation, and integration with CTCF/Cohesin loop anchors and enhancer annotations.

Limitations

The paper states that comparing Hi-C and FISH is limited because Hi-C read numbers are normalized between samples while FISH distances are absolute; it also notes that RNA-seq does not directly measure ongoing transcription rates and that limited Hi-C resolution prevents robust identification of small TADs.
The paper states that Tir1 transgene variegation upon differentiation limited analyses in committed cells, that CTCF-AID NPC subclones did not survive freeze-thawing, and that insulation did not reform after auxin washout in resting astrocytes.
The text makes evident that most experiments rely on mESCs and selected loci/cell types, that the AID fusion caused basal CTCF levels about 2–3-fold lower than parental cells, and that prolonged depletion produces secondary effects, so the study focuses on acute depletion during at least two days.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.cell.2017.05.004

Cites

102 of 102 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 21 cited sources checked · 0 supported · 0 flagged

Findingown data
CTCF depletion does not disrupt A/B compartmentalization.
“Surprisingly, active and inactive genome compartments remain properly segregated upon CTCF depletion, revealing that compartmentalization of mammalian chromosomes emerges independently of proper insulation of TADs.”
- Also stated in: § Disruption of Local Insulation Does Not Affect Higher-Order Chromosome Folding · hedged
  “Contact maps (Figure 4A) as well as compartment signal (Imakaev et al., 2012) indicated that compartmentalization and genomic location of the transitions between A-and B- compartments are maintained after CTCF depletion (Figure 4B-C and S4A).”
Quote in the paperSubstantial claim
Findingown data
CTCF does not bind the majority, about 80%, of transcription start sites of genes up-regulated after one day of depletion.
“The fact that in our data CTCF does not bind the majority (80%) of TSS of genes up-regulated after 1 day suggests CTCF normally represses them indirectly.”
Quote in the paperSubstantial claim
Findingown data
CTCF depletion causes a minor reproducible reduction of about 10% in compartmentalization strength.
“We detected a minor but reproducible reduction (∼10%) in the strength of compartmentalization upon CTCF depletion (Figure S4B).”
Quote in the paperSubstantial claim
Findingown data
Promoters of mis-regulated genes are more often close to loop anchors than promoters of non-regulated genes.
“Taking advantage of the Smc1a HiChIP data we noticed that promoters of mis-regulated genes are more often close to loop anchors than promoters of non-regulated genes (Figure S6D), while the distribution is similar outside of the anchors.”
Quote in the paperSubstantial claim
Findingown data
The CTCF motif at these transcription start sites is almost systematically oriented in the same direction as transcription, in 90% of unequivocal sites.
“Strikingly, the orientation of the CTCF motif at these TSSs is almost systematically in direct orientation with the direction of transcription (90% of unequivocal sites, Figure 6C and Supplementary Table 7).”
Quote in the paperNot a substantial claim

Findingcitation
TAD boundaries separate further apart in three-dimensional nuclear space upon CTCF loss.
“consistent with previous boundary-deletion experiments (Ji et al., 2016), TAD boundaries separate further apart in the three-dimensional space of the nucleus (Figure S3L).”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Ji et al., 2016
  Not checked in the free run.
Findingown data
CTCF depletion does not cause general chromatin compaction.
“Intra-TAD FISH distances were unaffected by CTCF depletion, indicating that loss of CTCF does not trigger general chromatin compaction.”
- Also stated in: § CTCF Binding Is Not a Direct Impediment to H3K27me3 Spreading in mESCs · plain
  “Overall chromosome compaction and organization are however not affected.”
Quote in the paperSubstantial claim
Findingown data
CTCF occupancy is lost or considerably lower at all binding sites after depletion.
“The enrichment level in persistent peaks was severely reduced (Figure S2D-E), indicating that CTCF occupancy is lost or considerably lower at all of its binding sites after depletion.”
Quote in the paperSubstantial claim
Findingown data
Of the 1000 CTCF-less residual boundaries, 609 had at least one CTCF ChIP-seq peak within 20 kb prior to depletion.
“From these 1000 CTCF-less residual boundaries 609 (61%) had at least one CTCF ChIP-seq peak +/- 1 bin (20kb) prior to depletion, suggesting that CTCF binding at these sites is not what initially drove local insulation.”
Quote in the paperSubstantial claim
Findingcitation
The AID-eGFP fusion causes slight constitutive destabilization, reducing basal CTCF levels about two- to three-fold compared with the untagged parental line.
“As reported previously the AID fusion led to slight constitutive destabilization (Morawska and Ulrich, 2013), so that basal CTCF levels were about 2–3-fold less in the AID-eGFP fusion line compared to the untagged parental line (Figure 1B and C).”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Morawska and Ulrich, 2013
  Not checked in the free run.
Findingown data
Acute CTCF depletion is tolerated for two days without obvious cell death or differentiation.
“Acute CTCF depletion was tolerated for 2 days without obvious cell death or differentiation (Figure 1F)”
Quote in the paperSubstantial claim
Findingown data
After two days of auxin, ChIP-seq detects only 27% of the initial CTCF peaks.
“Using ChIP-seq in CTCF-AID cells after 2 days of auxin we detected only 27% of the initial CTCF peaks.”
Quote in the paperSubstantial claim
Findingown data
CTCF depletion causes a local gain of H3K27me3 at initially bound CTCF sites.
“Changes were restricted to a very local gain of H3K27me3 signal at the initially bound CTCF site (Figure 7B and S7A), possibly due to nucleosomes becoming able to occupy the formerly bound CTCF site (Wiechens et al., 2016).”
Quote in the paperNot a substantial claim
Findingown data
The number of differentially expressed genes increases over ten-fold between day 1 and day 4 of CTCF depletion.
“The absolute number of differentially expressed genes increased over ten-fold between day 1 (370) and day 4 (4996) (Figure S6A-B)”
Quote in the paperNot a substantial claim
Findingown data
Immediately up-regulated genes tend to be located closer to active enhancers than down-regulated or non-regulated genes.
“We find that immediately up-regulated genes tend to be located genomically closer to active enhancers (Figure 6D and S6B) than down- or non-regulated genes.”
Quote in the paperSubstantial claim
Findingown data
Up-regulated genes after one day of CTCF depletion are enriched for having a TAD boundary between them and nearby active enhancers.
“However, a higher fraction of up-regulated genes normally have a TAD boundary separating them from neighboring (<200kb) enhancers, compared to down-regulated or non-regulated genes (Figure 6E and S6C).”
Quote in the paperSubstantial claim
Findingown data
Acute CTCF depletion down-regulates a subset of genes that have CTCF bound near their transcription start sites.
“Integration with CTCF Chip-exo data revealed that over 80% of the early down-regulated genes had CTCF bound within 1kb of the transcription start site (TSS) prior to depletion, as opposed to less than 20% of the up-regulated genes (Figure 6B).”
- Also stated in: § CTCF and transcriptional regulation · hedged
  “This indicates that the activity of a subset of CTCF-bound promoters (10% of all CTCF bound TSS) critically relies on CTCF, likely via direct binding.”
Quote in the paperSubstantial claim
Findingown data
CTCF is required for TAD organization in non-dividing cells.
“CTCF remains essential for TAD organization in non-dividing cells.”
- Also stated in: § Loss of CTCF also Triggers Misfolding in Non-Cycling Cells · plain
  “5C at the Xic revealed disrupted folding in cycling NPCs as well as resting ACs, whether CTCF was depleted before (Figure 5B-G) or after (Figure S5A-J) cell-cycle exit.”
Quote in the paperSubstantial claim
Findingown data
CTCF binding is not a direct barrier to H3K27me3 spreading in mouse embryonic stem cells.
“CTCF depletion did not trigger spreading of H3K27me3 as measured by ChIP-seq (Figure 7B-C), even after 4 days (3-4 cell divisions Figure S1B).”
- Also stated in: § CTCF Does Not Directly Constrain the Spread of H3K27me3 but May Still Define Chromatin Domains · plain
  “Our observation that H3K27me3 patterns remain largely unaltered challenges the notion that CTCF binding acts as a direct roadblock to heterochromatin spreading.”
Quote in the paperSubstantial claim
Findingown data
CTCF depletion does not alter the scaling of contact frequency with genomic distance.
“Scaling of contact frequencies as a function of genomic separation did not change either (Figure 4D).”
- Also stated in: § Introduction · boosted
  “CTCF depletion did not either alter how contact frequency scales overall with genomic distance, demonstrating that CTCF-mediated chromosomal interactions are not the ties that enable packaging of mammalian chromosomes.”
Quote in the paperSubstantial claim
Findingown data
Transcriptional activity was detected at 416 of the residual CTCF-less boundaries.
“Transcriptional activity (neighboring PolII ChIP-seq peak detected in untreated cells) was detected at 416 of the residual CTCF-less boundaries (41% - 2 fold enrichment over chance overlap).”
Quote in the paperNot a substantial claim
Findingown data
CTCF regains access to all cognate binding sites after transient depletion in mouse embryonic stem cells.
“ChIP-seq patterns from cells where auxin was washed off 2 days after a 2-day treatment was virtually identical to untreated cells, revealing that CTCF readily regains access to all of its cognate binding sites after transient depletion in mESCs (Figure S2B-E).”
Quote in the paperNot a substantial claim
Findingown data
Longer CTCF depletion dramatically slows cell proliferation.
“but depleting for longer slowed cell proliferation dramatically (Figure 1F and S1A-B).”
Quote in the paperNot a substantial claim
Findingown data
Of the 1000 CTCF-less residual boundaries, 103 are associated with an A/B compartment transition.
“Second, out of the 1000 CTCF-less residual boundaries only 103 (10% - 3.1 fold enrichment over chance overlap, Figure S3E-F) were associated with a transition between A- and B- compartments.”
Quote in the paperSubstantial claim
Findingown data
Immediate up-regulation after CTCF depletion is not coordinated for all genes of a domain across all TADs.
“However immediate up-regulation is not coordinated for all genes of the domain for all TADs.”
Quote in the paperSubstantial claim
Findingown data
CTCF depletion causes ectopic contacts across TAD boundaries visible by 5C as early as 24 hours.
“Our Hi-C maps revealed extensive ectopic contacts across initial TAD boundaries, clearly visible by 5C as early as 24h after CTCF depletion (about two cell divisions; Figure 3A and S3A-B).”
Quote in the paperSubstantial claim
Findingown data
The severity of TAD insulation defects scales with the degree of CTCF depletion.
“Insulation defects scaled with the degree of CTCF depletion and samples with around 15% CTCF preserved more insulation than completely depleted cells (with some boundaries more sensitive than others, Figure 5I-J).”
Quote in the paperSubstantial claim
Findingown data
CTCF depletion reduces inter-TAD 3D distances to levels equivalent to intra-TAD distances.
“For the two loci surveyed, loss of CTCF reduced inter-TAD 3D distances, which became equivalent to intra-TAD distances.”
Quote in the paperSubstantial claim
Findingown data
A subset of CTCF sites, about 7%, mark transitions in H3K27me3 enrichment in mouse embryonic stem cells.
“As reported in human cells (Cuddapah et al., 2009), we found that a subset of CTCF sites mark transitions in H3K27me3 enrichment in mESCs (∼7% of CTCF sites, Figure 7A).”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Cuddapah et al., 2009 source
  Not checked in the free run.
Findingown data
CTCF depletion efficiency is independent of local binding site density.
“Finally, depletion efficiency was equally efficient irrespective of local binding site density (Figure S2F-H).”
Quote in the paperNot a substantial claim
Findingown data
In the absence of CTCF, linear genomic coordinates become a better predictor of 3D distances.
“In the absence of CTCF, linear genomic coordinates become a better predictor of 3D distances (Figure S3K)”
Quote in the paperSubstantial claim
Findingown data
Acute depletion of CTCF in mouse embryonic stem cells causes loss of chromatin loops between CTCF-bound sites genome-wide.
“CTCF is absolutely and dose-dependently required for looping between CTCF target sites and insulation of topologically associating domains (TADs).”
- Also stated in: § CTCF is required for accumulating chromatin loops at CTCF sites · boosted
  “This confirmed that CTCF is required for the interaction between CTCF/Cohesin bound loop-anchor loci genome-wide, and that bringing CTCF back is sufficient to restore these preferential contacts (Figure 2C).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites Mumbach et al., 2016 source
  Not checked in the free run.
Findingown data
CTCF depletion reduces intra-TAD contacts measured by Hi-C.
“In line with earlier less impactful (Figure S3M) RNAi-mediated CTCF depletion (Zuin et al., 2014) we detected fewer intra-TAD contacts upon loss of CTCF by Hi-C, while FISH did not detect changes in intra-TAD compaction (Figure 3C-F).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites Zuin et al., 2014 source
  Not checked in the free run.
Findingown data
Up-regulated genes after one day of CTCF depletion tend to localize in the same TAD more often than expected by chance.
“This indicates that up-regulated genes tend to localize in the same TAD more often than by chance (p=0.0042, and p=0.19 for down-regulated genes -Methods).”
Quote in the paperSubstantial claim
Findingcitation
Affected-gene promoters showed no specific enrichment for tandem CTCF sites relative to their genome-wide frequency in CTCF ChIP-seq peaks.
“Promoters of affected genes were not specifically enriched for tandem CTCF sites compared to their occurrence in CTCF ChIP-seq peaks genome-wide (around 1/3 of peaks have multiple CTCF motifs (Pugacheva et al., 2015)).”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Pugacheva et al., 2015 source
  Not checked in the free run.
Findingown data
At stringent boundary thresholds, 62% of called boundaries matched previously identified loop anchors within ±1 20-kb bin.
“This comparison revealed that at high threshold values, corresponding to stricter boundary selection, up to 62% of detected boundaries co-aligned with the previously detected loop anchors within +-1 20kb bin precision.”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Mumbach et al., 2016 source
  Not checked in the free run.
Findingown data
Lowering the boundary detection threshold resulted in fewer additional boundaries co-aligning with loop anchors.
“As we lowered the boundary detection threshold, fewer added boundaries co-aligned with the loops”
Quote in the paperNot a substantial claim
Interpretationown data
In the absence of CTCF, neighboring TADs merge.
“In the absence of CTCF neighboring TADs merge, with consequences on transcriptional regulation.”
Quote in the paperSubstantial claim
Interpretationcitation
CTCF is a major blocking factor to the processivity of loop extrusion.
“Our observations are consistent with the proposed mechanisms of TAD formation by intra-TAD loop extrusion and are in agreement with the idea that CTCF is a major blocking factor to the processivity of extrusion (Fudenberg et al., 2016; Sanborn et al., 2015).”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites Fudenberg et al., 2016 source
  Not checked in the free run.
- cites Sanborn et al., 2015 source
  Not checked in the free run.
Interpretationcitation
Loops between TAD boundaries and TAD insulation are molecularly coupled.
“This substantiates the notion that these two aspects are molecularly coupled (Giorgetti et al., 2014).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites Giorgetti et al., 2014 source
  Not checked in the free run.
Interpretationown data
CTCF depletion triggers up-regulation of a subset of genes formerly insulated from neighboring enhancers by a TAD boundary.
“This suggests that CTCF depletion triggers up-regulation of a subset of genes formerly insulated from neighboring enhancers by a TAD boundary.”
Quote in the paperSubstantial claim
Interpretationown data
Factors other than CTCF control basal chromatin packaging and A/B compartment segregation.
“Factors other than CTCF must therefore control the basal packaging regime of chromatin as well as its segregation in A- and B-compartments.”
Quote in the paperSubstantial claim
Interpretationown data
CTCF mediates enhancer-blocking insulation through the specification of TAD boundaries.
“This observation supports at the genome-wide level the notion that CTCF can mediate enhancer-blocking insulation through the specification of TAD boundaries, in line with previous locus-specific studies (Dowen et al., 2014; Doyle et al., 2014; Lupiáñez et al., 2015; Nora et al., 2012).”
- Also stated in: § CTCF Does Not Directly Constrain the Spread of H3K27me3 but May Still Define Chromatin Domains · plain
  “Altogether current data support that CTCF mediates enhancer-blocker activity, through its ability to mediate insulation and segmental folding into TADs, but is not a direct impediment to heterochromatin spreading.”
Quote in the paperSubstantial claim0 of 3 sources checked
- cites Dowen et al., 2014 source
  Not checked in the free run.
- cites Doyle et al., 2014 source
  Not checked in the free run.
- cites Lupiáñez et al., 2015 source
  Not checked in the free run.
Interpretationown data
Compartmentalization of mammalian chromosomes does not depend on proper TAD insulation.
“revealing that compartmentalization of mammalian chromosomes emerges independently of proper insulation of TADs.”
- Also stated in: § Local Insulation and A/B Compartmentalization Are Molecularly Separable Principles of Mammalian Genome Folding · plain
  “We conclude that proper packaging of chromatin into TADs is not a prerequisite for the segregation of A and B compartments.”
Quote in the paperSubstantial claim
Interpretationown data
CTCF is a major determinant of mammalian chromosome folding.
“We demonstrate that CTCF is a major determinant of mammalian chromosome folding.”
Quote in the paperSubstantial claim
Interpretationown data
Transient CTCF loss can trigger irreversible transcriptional changes in a small subset of genes, suggesting positive feedback.
“However, while some transcripts showed a trend downward their initial values while others kept rising (Supplementary Table 3), suggesting that for a small subset of genes transient loss of CTCF depletion can trigger transcriptional changes that become irreversible, indicating they are involved in a positive feedback mechanism.”
Quote in the paperNot a substantial claim
Interpretationown data
Promoters at loop anchors and TAD borders are more sensitive to CTCF disruption than genes away from boundaries.
“This indicates that promoters at loop anchors and TAD borders are more sensitive to CTCF disruption than genes away from boundaries.”
Quote in the paperSubstantial claim
Interpretationown data
Down-regulation after CTCF depletion cannot be explained by loss of direct looping between promoters and enhancers.
“Therefore down-regulation cannot be explained by loss of direct looping between promoters and enhancers.”
Quote in the paperSubstantial claim
Interpretationown data
CTCF binding confers the insulated nature of mammalian TADs.
“Our data support at the genome-wide level that CTCF binding confers the insulated nature of mammalian TADs, corroborating earlier boundary deletion experiments.”
Quote in the paperSubstantial claim
Interpretationown data
CTCF has an activator effect through direct promoter binding.
“our observations also reveal an important activator effect of CTCF through direct promoter binding”
Quote in the paperSubstantial claim
Interpretationown data
CTCF's role in chromosome folding is restricted to sub-megabase genome organization.
“Its role is however restricted to sub-megabase genome organization”
Quote in the paperSubstantial claim
Interpretationown data
CTCF-mediated chromosomal interactions are not the ties that enable packaging of mammalian chromosomes.
“demonstrating that CTCF-mediated chromosomal interactions are not the ties that enable packaging of mammalian chromosomes.”
Quote in the paperSubstantial claim
Interpretationown data
Local insulation and higher-order compartmentalization rely on distinct molecular determinants.
“CTCF depletion did not disrupt A/B compartments, revealing that local insulation and higher-order compartmentalization rely on distinct molecular determinants.”
Quote in the paperSubstantial claim
Interpretationreasoning
TADs and compartments do not represent a hierarchy in the folding of mammalian chromosomes.
“TADs and compartments therefore do not represent a hierarchy in the folding of mammalian chromosomes.”
Quote in the paperSubstantial claim
Interpretationown data
Strong Tir1 expression is essential for auxin responsiveness.
“Robust expression of the Tir1 transgene was absolutely critical to mediate auxin responsiveness.”
Quote in the paperNot a substantial claim
Interpretationcitation
The Tigre locus supports higher expression of the Tir1 transgene.
“suggesting that Tigre allows for higher expression or the Tir1 transgene, as reported previously (Madisen et al., 2015).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites Madisen et al., 2015 source
  Not checked in the free run.

May combine two claims. 24
Classified as probably not a substantial claim. 23

May combine two claims.
Findingown data
A subset of TAD boundaries, about 18% or 1000 boundaries, persists after CTCF depletion and is less affected.
“After removing those that displayed residual CTCF binding by ChIP-seq we identified 1000 persistent CTCF-less boundaries (18% of initial boundaries), where insulation was much less affected by CTCF depletion (Figure 3B).”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
Over 80% of early down-regulated genes had CTCF bound within 1 kb of their transcription start site before depletion, compared with less than 20% of up-regulated genes.
“Integration with CTCF Chip-exo data revealed that over 80% of the early down-regulated genes had CTCF bound within 1kb of the transcription start site (TSS) prior to depletion, as opposed to less than 20% of the up-regulated genes (Figure 6B).”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
Auxin washout restores insulated TADs in mouse embryonic stem cells and neural precursor cells but not in resting astrocytes.
“Washing off auxin led to reformation of insulated TADs in mESCs and NPCs but not resting astrocytes.”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
Auxin washout after two days of CTCF depletion does not fully restore the transcriptome; most differentially expressed genes remain up-regulated.
“Auxin washoff after a 2-day treatment did not completely restore the transcriptome, with most (252 out of 278, 90%) of the differentially expressed genes remaining up-regulated compared to untreated cells (Figure 6A-B).”
Quote in the paperSubstantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown data
At each time point, about half of the dysregulated genes are down-regulated and half are up-regulated.
“with around half of the dysregulated being down-regulated and half up-regulated at each time-point.”
Quote in the paperNot a substantial claim
May combine two claims.
Findingown data
CTCF depletion is maximal by 3 hours 45 minutes after auxin addition, and recovery is half complete by 15 hours after washout.
“CTCF depletion was maximal as early as 3h45 after adding auxin (Figure 1E).”
- Also stated in: § Acute CTCF Depletion with the Auxin-Inducible Degron System · plain
  “Recovery initiated readily after washoff and was half complete by 15h (Figure 1E).”
Quote in the paperNot a substantial claim
May combine two claims.
Findingown data
Restoring CTCF after depletion restores chromatin loops and TAD insulation.
“Restoring CTCF reinstates proper architecture on altered chromosomes, indicating a powerful instructive function for CTCF in chromatin folding.”
- Also stated in: § CTCF is required for accumulating chromatin loops at CTCF sites · plain
  “In contrast, auxin-mediated depletion of CTCF led to complete disappearance of these 5C peaks while auxin washoff restored them (Figure S2I).”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
CTCF depletion in mouse embryonic stem cells does not block the cell cycle, induce DNA damage, or cause aneuploidy.
“Importantly, CTCF depletion in mESCs did not block cells in a specific phase of the cell cycle, and did not induce DNA damage or aneuploidy (Supplementary figures 1D-E).”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
Folding defects after CTCF depletion are somewhat less pronounced in differentiated cells, correlating with switching of the surveyed region into a lamina-associated domain.
“Folding defects appeared somewhat less pronounced in differentiated cells, correlating with switching of a large portion of the region surveyed into a lamina associated domain (LAD) – and presumably B compartment (Figure 5A-D).”
Quote in the paperNot a substantial claim
May combine two claims.
Findingcitation
Auxin-mediated degradation of CTCF prevents subcloning of CTCF-AID cells, recapitulating the full CTCF knockout phenotype in mouse embryonic stem cells.
“In contrast, auxin-mediated degradation of CTCF prevented subcloning of CTCF-AID cells, recapitulating the full CTCF knockout phenotype in mESCs (Sleutels et al., 2012) (Figure 1D).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites Sleutels et al., 2012 source
  Not checked in the free run.
May combine two claims.
Findingown data
CTCF depletion causes loss of insulation at most TAD boundaries, affecting over 80% of boundaries.
“Loss of CTCF led to loss of insulation at most boundaries (>80%, Figure 3B).”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
At immediately down-regulated genes, CTCF is bound about 60 bp upstream of the transcription start site and demarcates the beginning of the nucleosome-depleted region.
“We noticed that at the promoter of the immediately down-regulated genes CTCF is bound slightly upstream of the TSS (around 60bp) and demarcates the beginning of the nucleosome-depleted region (Figure 6C).”
Quote in the paperSubstantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown data
CTCF depletion causes a slight but significant decrease in overall H3K27me3 levels.
“On a more global scale, we observed a slight but significant decrease in overall H3K27me3 levels (Figure S7B).”
Quote in the paperNot a substantial claim
May combine two claims.
Findingown data
Auxin treatment alone does not affect untagged mouse embryonic stem cells or their gene activity.
“Auxin in itself was neutral to untagged mESCs (Figure 1D and E), with no differential gene activity detected after up to 4 days of treatment (Supplementary tables 2 and 3).”
Quote in the paperSubstantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown data
Basal CTCF-AID-eGFP levels were 1.5- to 2-fold lower when Tir1 was inserted at Tigre than when it was inserted at Rosa26 or randomly.
“Basal CTCF-AID-eGFP levels were slightly lower (1.5-2 fold) than when Tir1 was inserted at Rosa26 or randomly (Figure S3C)”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingcitation
The AID* tag depletes CTCF with efficiency equivalent to that of the original full-length 231-amino-acid AID tag.
“We observed equivalent CTCF depletion efficiency with the AID* as with the original full-length 231 amino-acid tag (Nishimura et al., 2009) (data not shown).”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Nishimura et al., 2009 source
  Not checked in the free run.
May combine two claims.
Findingown data
Tir1 expression from the transgene became variegated during differentiation, causing heterogeneous auxin response and limiting analyses in committed cells that could be subcloned.
“The Tir1 transgene variegated upon differentiation, which we overcame by first converting CTCF-AID mESCs into self-renewing Neural Precursor Cells (NPCs), subcloning NPCs and then selecting clonal lines that retained homogenous CTCF degradation upon auxin treatment.”
- Also stated in: § Gene targeting · plain
  “Indeed our CTCF-AID lines down-regulated Tir1 during differentiation, even when targeted at Rosa26, leading to variegation of auxin response and limiting our analyses in committed cells that can be subcloned, such as neural progenitors.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown data
Only a few resistant clones were recovered after Tir1 knock-in, which suggested sub-optimal targeting.
“We noticed that only a handful of resistant clones were recovered, suggesting sub-optimal targeting – either because of the sgRNA or the targeting construct.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown data
Tir1 targeting with the Tigre vector was at least five times more efficient than with the Rosa26 vector.
“We noticed that Tir1 targeting with the Tigre targeting vector was at least 5-fold more efficient than with our Rosa26 targeting vector.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingreasoning
The improved 5C protocol reduces the number of cells required by 5- to 10-fold and shortens the protocol from 8 days to 4 days.
“These changes enable proceeding through the 3C protocol in a single tube per sample, allow handling of over 20 samples in parallel, reduce the amount of cells needed by a factor 5 to 10 and cut down the time needed to complete the protocol from 8 days (Nora et al. 2012) to 4 days.”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Nora et al. 2012 source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown data
The dual Cas9 nickase strategy performed poorly for targeting the Rosa26 locus.
“We noticed the dual nickase underperformed for Rosa26 and recommend using a single nuclease strategy approach with the first sgRNA only.”
Quote in the paperNot a substantial claim
May combine two claims.
Interpretationreasoning
Cohesin packages the chromatin fiber while CTCF defines focal boundaries by constraining this packaging activity.
“The emerging model is that Cohesin packages the chromatin fiber while CTCF defines focal boundaries by constrains this packaging activity.”
Quote in the paperSubstantial claim
May combine two claims.
Interpretationown data
Either compartment transition or transcription alone is not sufficient to drive CTCF-independent insulation.
“While this is compatible with compartment transition or transcription participating in the maintenance of CTCF-independent insulation, either of these features alone is not sufficient to drive CTCF-independent insulation since most boundaries associated with them are affected by CTCF depletion (Supplementary Table 6).”
Quote in the paperSubstantial claim
May combine two claims.
Interpretationreasoning
The extrusion model describes mammalian chromosome folding at the sub-megabase scale but does not account for genomic compartment segregation.
“Notably, the extrusion model accurately describes mammalian chromosome folding at the sub-megabase scale but does not account for the segregation of genomic compartments, and the direct molecular drivers of CTCF-independent higher-order compartmentalization remain to be defined.”
Quote in the paperSubstantial claim
May combine two claims.
Interpretationcitation
Depleting CTCF does not affect contact frequency scaling, unlike altering factors that control Cohesin turnover such as Nipbl.
“This would explain why depleting CTCF does not affect how the frequency of chromosomal contacts scales overall with genomic distance, as opposed to altering factors that control Cohesin turnover on chromatin, such as Nipbl (Schwarzer et al., 2016).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites Schwarzer et al., 2016
  Not checked in the free run.
May combine two claims.
Interpretationown data
The H3K27me3 changes upon CTCF depletion are likely indirect and may be explained by reduced EED expression.
“These changes are likely indirect effects as they are not restricted to the vicinity of CTCF sites, and may be accounted for by 2-fold transcriptional down-regulation of the essential PRC2 component EED (Supplementary Table 3).”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown data
The efficiency of Hi-C ligation product formation and biotin fill-in ranged from 50% to 80% across different Hi-C libraries.
“The relative efficiency of Hi-C ligation product formation and biotin fill-in was defined as the proportion of ligation product digested with NheI and varied from 50 to 80% in different Hi-C libraries.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown data
The optimal boundary detection threshold was 0.3, at which the specificity of loop anchor recall dropped threefold.
“this analysis suggested the optimal threshold of 0.3, where the specificity of loop anchor recall dropped 3-fold.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown data
NheI digestion quality control showed that the majority of Hi-C ligation products were digested and that the libraries consisted mainly of true ligation products.
“It indicated that the majority of the ligation products have been digested by NheI and validated that the libraries were mainly constituted of true ligation products.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown data
More than 95% of cells had one knock-in allele, and 20% of those were homozygous.
“Over 95% of cells had one knock-in allele, of which 20% were homozygous.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown data
The CTCF-AID-eGFP, Tir1 clone used in the study had a randomly inserted Tir1 cassette.
“Rosa26 PCR genotyping revealed this clone had undergone random insertion of the Tir1 cassette.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown data
The clone used for doxycycline-inducible CTCF expression was homozygous for the integration and still carried the puromycin cassette.
“The clone analyzed here was homozygous for the integration and the puro cassette was still present in the final cell line.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given
Auxin was added to dissociation, wash, and flow buffers to prevent re-expression of the CTCF-AID-eGFP fusion.
“Dissociation, wahs and Flow buffers were supplemented with auxin, when appropriate, to avoid re-expression of the CTCF-AID-eGFP fusion.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown data
Negative controls lacking ligase, template, or 5C oligonucleotide were included in every 5C experiment to check for contamination.
“Negative controls (no ligase, no template, no 5C oligonucleotide) were included during each experiments to ensure the absence of contamination.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitation
Peak calling followed the guidelines of Thomas et al. (2016).
“For peak calling we followed the guidelines described in (Thomas et al., 2016).”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites Thomas et al., 2016 source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given
The CTCF-AID neural progenitor subclones did not survive freezing and thawing.
“The CTCF-AID NPC subclones did not survive freeze and thawing.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation
The AID* tag, a 44-amino-acid truncation developed in yeast, is the smallest functional AID tag and is shorter than the 67-amino-acid mini-AID.
“We used the smallest functional truncation of the AID tag (AID*, 44 amino-acids), initially developed in yeast (Morawska and Ulrich, 2013), shorter than the mini-AID (67 amino-acids (Kubota et al., 2013)).”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites Morawska and Ulrich, 2013
  Not checked in the free run.
- cites Kubota et al., 2013 source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown data
Half of the clones had undergone FlpO-mediated recombination, and homozygous clones always had recombination on both alleles.
“Half of the clones were found to have undergone FlpO-mediated recombination. When homozygous both alleles always underwent recombination.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given
The consensus ChIP-seq peak list was defined by keeping only peaks that overlapped by at least one base pair between biological replicates.
“The consensus peak list was obtained by retaining peaks that overlapped for at least 1bp between biological replicates.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given
The FPKM values in Supplementary Table 3 are means from three independent biological replicates.
“FPKM provided in Supplementary Table 3 are means from 3 independent biological replicates.”
Quote in the paperNot a substantial claim
Classified as probably not a substantial claim.
Study design and conductown data
The clone with the fewest GFP-positive cells, less than 1% after 24 hours of auxin treatment, was selected.
“We selected the clone with the fewest GFP-positive cells (<1%) after 24h of auxin treatment.”
Quote in the paperSubstantial claim

41 of 41

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Depleting RAD21 or CTCF also down-regulated Car2.
“Depleting RAD21 or CCCTC-binding factor (CTCF) also down-regulated Car2 (fig. S12C) (7, 30)”
From Synergy between regulatory elements can render cohesin dispensable for distal enhancer function (2026) · cites this paper as [30]
In Results, ‘CTCF and transcriptional regulation’ (page unavailable), the paper reports that CTCF depletion down-regulated a subset of genes in mouse embryonic stem cells. Our copy does not identify Car2 among them, so it does not establish the gene-specific claim. The paper also does not report RAD21 depletion; with two citations attached to the sentence, that part may be attributed to the other source. (LLM, conf=0.78)
Experimental — accuracy not yet measured
Temporary disruption of 3D loops on a genome-wide scale through cohesin depletion has minimal lasting effect on gene expression.
“Finally, the temporary disruption of 3D loops on a genome-wide scale through cohesin depletion was found to have minimal lasting effect on gene expression155,156.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [156]
The Results section on chromatin loops reports genome-wide loss of CTCF/cohesin-bound loop contacts after CTCF depletion, and the Discussion describes limited immediate transcriptional effects. But this paper depleted CTCF, not cohesin, and its Results section on transcriptional regulation says most differentially expressed genes remained up-regulated after washout. It therefore does not support the claim of minimal lasting effects from cohesin depletion. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Deletion or degradation of cohesin or CTCF in differentiated cells has only mild effects on gene expression.
“Surprisingly however, deletion or degradation of cohesin or CTCF in differentiated cells has only mild effects on gene expression [344–349].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [346]
The Discussion (‘TAD Insulation and Transcriptional Regulation’; page unavailable) describes the immediate transcriptional effects of CTCF depletion as ‘rather limited’ and ‘initially mild.’ But the experiments were in mouse embryonic stem cells, not differentiated cells; the Results also report substantially more differentially expressed genes after four days. This paper does not establish the claimed mild gene-expression effects of cohesin loss in differentiated cells. (LLM, conf=0.90)
Experimental — accuracy not yet measured
A/B compartment structure does not disappear (and is in fact even strengthened) upon cohesin/CTCF depletion, but, like TADs, dissolves in mitosis.
“The A/B compartment structure does not disappear (and is in fact even strengthened) upon cohesin/CTCF depletion [344, 346–348], but, like TADs, dissolves in mitosis [459].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [346]
The Results section, “Disruption of Local Insulation Does Not Affect Higher-Order Chromosome Folding,” reports that A/B compartmentalization is maintained after CTCF depletion. It also reports a minor (~10%) reduction in compartmentalization strength, not strengthening. This paper does not directly test cohesin depletion; the mitosis clause has a separate citation. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Rapid depletion of cohesin or CTCF quickly abolishes TADs but has only relatively mild effects on gene expression.
“rapid depletion of cohesin or CTCF quickly abolishes TADs but, as mentioned above, has only relatively mild effects on gene expression [301, 345–347, 448].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [346]
The Results section reports that CTCF depletion caused loss of insulation at more than 80% of TAD boundaries, and the Discussion describes rather limited immediate transcriptional effects. But 18% of boundaries persisted, so saying TADs were abolished overstates the finding. This paper directly tests CTCF depletion; it mentions cohesin depletion in a parallel study rather than testing it here. (LLM, conf=0.84)
Experimental — accuracy not yet measured

Convergent binding sites for CTCF located at TAD borders block the movement of loop extruders.
“Convergent binding sites for the versatile transcription factor CTCF (CCCTC-binding factor) located at TAD borders [46] block the movement of loop extruders [47,48,49].”
From Enhancer Function in the 3D Genome (2023) · cites this paper as [47]
The data are consistent with a previous report that genome compartmentalization is preserved after depletion of cohesin or CTCF.
“Our data is consistent with a previous report that genome compartmentalization is preserved after depletion of cohesin (Seitan et al., 2013) or CTCF (Nora et al., 2017).”
From Cohesin Loss Eliminates All Loop Domains (2017) · cites this paper as Nora et al., 2017
Their data for cohesin depletion is consistent with the study by Nora et al., 2017.
“Our data for cohesin depletion is consistent with is study.”
From Cohesin Loss Eliminates All Loop Domains (2017) · cites this paper as Nora et al., 2017
Loop extrusion mediated by cohesin and CTCF mediates the formation of chromatin loops and self-interacting TADs.
“loop extrusion mediated by cohesin and CTCF mediates the formation of chromatin loops and self-interacting Topologically Associating Domains (TADs)”
From Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration (2023) · cites this paper as [86]
Domains and compartment formation can be at least partially uncoupled and may result from different biological phenomena.
“recent evidence indicates that domains and compartment formation can be at least partially uncoupled and may result from different biological phenomena (Nora et al., 2017).”
From Multiscale 3D Genome Rewiring during Mouse Neural Development (2017) · cites this paper as Nora et al., 2017
Architectural proteins such as CTCF and cohesin play a role in domain formation.
“It is known that architectural proteins such as CTCF and cohesin play a role (Haarhuis et al., 2017, Nora et al., 2017, Phillips-Cremins et al., 2013)”
From Multiscale 3D Genome Rewiring during Mouse Neural Development (2017) · cites this paper as Nora et al., 2017
Polymer simulation studies and Hi-C studies employing acute depletion of CTCF and cohesin support a dynamic model of TADs and chromatin loops.
“complementary polymer simulation studies and Hi-C studies employing acute depletion of CTCF and cohesin, which also support such a dynamic model.”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [10]
∼18% of TAD boundaries appear to be partially resistant to CTCF loss, suggesting that additional boundary factors, such as active promoters and alternative architectural factors, may also play a role.
“Finally, ∼18% of TAD boundaries appear to be partially resistant to CTCF loss,10 suggesting that additional boundary factors, such as active promoters4 since engaged RNA Pol II can block cohesin extrusion46 as well as alternative architectural factors, may also play a role.”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [10]
CTCF loss has only a small effect on epigenomic compartments, whereas cohesin loss increases the degree of epigenomic compartmentalization ∼2-fold.
“Likewise, CTCF loss has only a small effect on epigenomic compartments,10 whereas cohesin loss increases the degree of epigenomic compartmentalization ∼2-fold.11,13”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [10]
Recent studies employing induced CTCF and cohesin degradation now strongly support a model where cohesin forms TADs and CTCF establishes TAD boundaries.
“In conclusion, recent studies10–15 employing induced CTCF and cohesin degradation now strongly support a model where cohesin forms TADs and CTCF establishes TAD boundaries.”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [10]
CTCF loss has essentially no effect on genome-averaged contact probability at any distance scale, whereas cohesin loss significantly reduces contact probability at the scale of tens to hundreds of kilobases.
“Consistent with their different roles, CTCF loss has essentially no effect on genome-averaged contact probability at any distance scale,10 whereas cohesin loss significantly reduces contact probability at the scale of tens to hundreds of kilobases,11”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [10]
TADs and well-defined Hi-C loops largely disappear when either CTCF or cohesin is strongly depleted, but for different reasons.
“In accordance with the extrusion model, TADs and well-defined Hi-C loops largely disappear when either CTCF10,14 or cohesin11,13–15 is strongly depleted, but for different reasons.”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [10]
CTCF and cohesin are required for chromatin looping, form a biochemically stable protein complex, and both bind chromatin at loop anchors.
“In summary, CTCF and cohesin are required for chromatin looping,10–15 form a biochemically stable protein-complex and both bind chromatin at loop anchors.”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [10]
Chromatin is still compacted and extruded by cohesin, but without sharp boundaries, TADs disappear in Hi-C maps.
“Thus, chromatin is still compacted and extruded by cohesin, but without sharp boundaries, TADs disappear in Hi-C maps.10,14”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [10]
Since multiple studies show that TADs and chromatin loops disappear without CTCF and cohesin, the most stable protein of CTCF and cohesin should set an upper limit on the stability of TADs and chromatin loops.
“Since multiple studies show that TADs and chromatin loops disappear without CTCF10,14 and cohesin,11,13–15 we reasoned that the most stable protein of CTCF and cohesin should set an upper limit on the stability of TADs and chromatin loops.”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [10]
CTCF and cohesin both appear absolutely required for the formation of most TADs.
“although CTCF and cohesin both appear absolutely required for the formation of most TADs10-15”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [10]
Dynamic loop extrusion models can explain recent perturbation experiments where CTCF binding sites have been added or deleted and also explain the loss of either CTCF or cohesin.
“Notably, a key advantage of dynamic loop extrusion models is that they can explain recent perturbation experiments where CTCF binding sites have been added or deleted9,49-51 and also explain the loss of either CTCF or cohesin.10-15”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [10]
About 18% of TAD boundaries were not sensitive to CTCF loss and could have different dynamics.
“(∼18% of TAD boundaries were not sensitive to CTCF loss10 and could have different dynamics)”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [10]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

RecJf digestion step specifies lambda exonuclease
Minor
The step is described as RecJf exonuclease digestion and uses RecJf buffer, but the enzyme specified for that step is lambda exonuclease.
CTCF tag placement differs between Results and Methods
Minor
The Results say the AID-eGFP tag was introduced at the Ctcf stop codon, but the gene-targeting Methods say it was knocked in at the N-terminus of CTCF.
Different Tir1 targeting vectors specified for cell line #1
Minor
The plasmid-construction Methods identify pEN113 as the Tir1 vector for cell line #1, whereas the gene-targeting Methods say pEN114 was used to introduce Tir1 into the line subsequently identified as #1.

3 of 3

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Fast gapped-read alignment with Bowtie 2
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STAR: ultrafast universal RNA-seq aligner
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Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation
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Multiplex Genome Engineering Using CRISPR/Cas Systems
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Self-citation
Topological domains in mammalian genomes identified by analysis of chromatin interactions
Dixon, J. R., Selvaraj, S., Yue, F., Kim, A., Li, Y., Shen, Y., Hu, M., Liu, J. S., & Ren, B. (2012) · Nature · doi:10.1038/nature11082 · Cited by 6,829 · see citing works
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Super-enhancers in the control of cell identity and disease
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Self-citation
Disruptions of Topological Chromatin Domains Cause Pathogenic Rewiring of Gene-Enhancer Interactions
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Self-citation
Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions
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Self-citation
Iterative correction of Hi-C data reveals hallmarks of chromosome organization
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“This highlights the crucial role of boundaries in mediating the physical insulation of neighboring chromosome domains, with important implications for disease-causing chromosomal rearrangements in humans (Flavahan et al., 2016; Franke et al., 2016; Hnisz et al., 2016).”
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Self-citation
Cohesin mediates transcriptional insulation by CCCTC-binding factor
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Architectural protein subclasses shape 3D organization of genomes during lineage commitment
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Chromosome Conformation Capture Carbon Copy (5C): A massively parallel solution for mapping interactions between genomic elementsPreprint
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Organization and function of the 3D genome
Bonev, B., & Cavalli, G. (2016) · Nature Reviews Genetics · doi:10.1038/nrg.2016.112 · Cited by 1,174 · see citing works
HiChIP: efficient and sensitive analysis of protein-directed genome architecture
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Transgenic mice for intersectional targeting of neural sensors and effectors with high specificity and performance
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Molecular Maps of the Reorganization of Genome-Nuclear Lamina Interactions during Differentiation
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Activation of proto-oncogenes by disruption of chromosome neighborhoods
Hnisz, D., Weintraub, A. S., Day, D. S., Valton, A.-L., Bak, R. O., Li, C. H., Goldmann, J., Lajoie, B. R., Fan, Z. P., Sigova, A. A., et al. (2016) · Science · doi:10.1126/science.aad9024 · Cited by 1,042 · cited 1× · see citing works
“This highlights the crucial role of boundaries in mediating the physical insulation of neighboring chromosome domains, with important implications for disease-causing chromosomal rearrangements in humans (Flavahan et al., 2016; Franke et al., 2016; Hnisz et al., 2016).”
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CTCF-Mediated Human 3D Genome Architecture Reveals Chromatin Topology for Transcription
Tang, Z., Luo, O. J., Li, X., Zheng, M., Zhu, J. J., Szalaj, P., Trzaskoma, P., Magalska, A., Wlodarczyk, J., Ruszczycki, B., et al. (2015) · Cell · doi:10.1016/j.cell.2015.11.024 · Cited by 982 · see citing works
Organization of the mitotic chromosome
Naumova, N., Imakaev, M., Fudenberg, G., Zhan, Y., Lajoie, B. R., Mirny, L. A., & Dekker, J. (2013) · Science · doi:10.1126/science.1236083 · Cited by 976 · cited 2× · see citing works
“One tube was kept separate and used for generating a 3C control library as described (Naumova et al., 2013).”
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Condensin-driven remodelling of X chromosome topology during dosage compensation
Crane, E. E., Bian, Q., McCord, R. P., Lajoie, B. R., Wheeler, B. S., Ralston, E. J., Uzawa, S., Dekker, J., & Meyer, B. J. (2015) · Nature · doi:10.1038/nature14450 · Cited by 972 · see citing works
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CRISPR Inversion of CTCF Sites Alters Genome Topology and Enhancer/Promoter Function
Guo, Y., Xu, Q., Canzio, D., Shou, J., Li, J., Gorkin, D. U., Jung, I., Wu, H., Zhai, Y., Tang, Y., et al. (2015) · Cell · doi:10.1016/j.cell.2015.07.038 · Cited by 958 · see citing works
Cohesins Functionally Associate with CTCF on Mammalian Chromosome Arms
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Control of cell identity genes occurs in insulated neighborhoods in mammalian chromosomes
Dowen, J. M., Fan, Z. P., Hnisz, D., Ren, G., Abraham, B. J., Zhang, L. N., Weintraub, A. S., Schuijers, J., Lee, T. I., Zhao, K., et al. (2014) · Cell · doi:10.1016/j.cell.2014.09.030 · Cited by 884 · see citing works
Cohesin and CTCF differentially affect chromatin architecture and gene expression in human cells
Zuin, J., Dixon, J. R., van der Reijden, M. I. J. A., Ye, Z., Kolovos, P., Brouwer, R. W. W., van de Corput, M. P. C., van de Werken, H. J. G., Knoch, T. A., van IJcken, W. F. J., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1317788111 · Cited by 779 · see citing works
Genome Architecture: Domain Organization of Interphase Chromosomes
Bickmore, W. A., & van Steensel, B. (2013) · Cell · doi:10.1016/j.cell.2013.02.001 · Cited by 725 · see citing works
The Hierarchy of the 3D Genome
Gibcus, J. H., & Dekker, J. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.02.011 · Cited by 695 · see citing works
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Comparative Hi-C Reveals that CTCF Underlies Evolution of Chromosomal Domain Architecture
Vietri Rudan, M., Barrington, C., Henderson, S., Ernst, C., Odom, D. T., Tanay, A., & Hadjur, S. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.02.004 · Cited by 680 · see citing works
CTCF mediates long-range chromatin looping and local histone modification in the β-globin locus
Splinter, E., Heath, H., Kooren, J., Palstra, R.-J., Klous, P., Grosveld, F., Galjart, N., & de Laat, W. (2006) · Genes & Development · doi:10.1101/gad.399506 · Cited by 677 · see citing works
Formation of new chromatin domains determines pathogenicity of genomic duplications
Franke, M., Ibrahim, D. M., Andrey, G., Schwarzer, W., Heinrich, V., Schöpflin, R., Kraft, K., Kempfer, R., Jerković, I., Chan, W.-L., et al. (2016) · Nature · doi:10.1038/nature19800 · Cited by 673 · see citing works
CTCF Binding Polarity Determines Chromatin Looping
de Wit, E., Vos, E. S. M., Holwerda, S. J. B., Valdes-Quezada, C., Verstegen, M. J. A. M., Teunissen, H., Splinter, E., Wijchers, P. J., Krijger, P. H. L., & de Laat, W. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.09.023 · Cited by 641 · see citing works
Global analysis of the insulator binding protein CTCF in chromatin barrier regions reveals demarcation of active and repressive domains
Cuddapah, S., Jothi, R., Schones, D. E., Roh, T.-Y., Cui, K., & Zhao, K. (2009) · Genome Research · doi:10.1101/gr.082800.108 · Cited by 637 · see citing works
Evolutionarily conserved replication timing profiles predict long-range chromatin interactions and distinguish closely related cell typesPreprint
Ryba, T., Hiratani, I., Lu, J., Itoh, M., Kulik, M. J., Zhang, J., Schulz, T. C., Robins, A. J., Dalton, S., & Gilbert, D. M. (2010) · Genome Research · doi:10.1101/gr.099655.109 · Cited by 608 · see citing works
CTCF establishes discrete functional chromatin domains at the <i>Hox</i> clusters during differentiation
Narendra, V., Rocha, P. P., An, D., Raviram, R., Skok, J. A., Mazzoni, E. O., & Reinberg, D. (2015) · Science · doi:10.1126/science.1262088 · Cited by 535 · see citing works
CTCF physically links cohesin to chromatin
Rubio, E. D., Reiss, D. J., Welcsh, P. L., Disteche, C. M., Filippova, G. N., Baliga, N. S., Aebersold, R., Ranish, J. A., & Krumm, A. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0801273105 · Cited by 511 · see citing works
CTCF and Cohesin in Genome Folding and Transcriptional Gene Regulation
Merkenschlager, M., & Nora, E. P. (2016) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-083115-022339 · Cited by 505 · see citing works
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Chromatin Architecture of the Human Genome
Gilbert, N., Boyle, S., Fiegler, H., Woodfine, K., Carter, N. P., & Bickmore, W. A. (2004) · Cell · doi:10.1016/j.cell.2004.08.011 · Cited by 494 · see citing works
eulerAPE: Drawing Area-Proportional 3-Venn Diagrams Using Ellipses
Micallef, L., & Rodgers, P. J. (2014) · PLoS ONE · doi:10.1371/journal.pone.0101717 · Cited by 493 · see citing works
Genome-wide Maps of Nuclear Lamina Interactions in Single Human Cells
Kind, J., Pagie, L., de Vries, S., Nahidiazar, L., Dey, S. S., Bienko, M., Zhan, Y., Lajoie, B. R., de Graaf, C. A., Amendola, M., et al. (2015) · Cell · doi:10.1016/j.cell.2015.08.040 · Cited by 467 · see citing works
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Predictive polymer modeling reveals coupled fluctuations in chromosome conformation and transcription
Giorgetti, L., Galupa, R., Nora, E. P., Piolot, T., Lam, F., Dekker, J., Tiana, G., & Heard, E. (2014) · Cell · doi:10.1016/j.cell.2014.03.025 · Cited by 460 · cited 2× · see citing works
“This substantiates the notion that these two aspects are molecularly coupled (Giorgetti et al., 2014).”
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Modeling epigenome folding: formation and dynamics of topologically associated chromatin domains
Jost, D., Carrivain, P., Cavalli, G., & Vaillant, C. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku698 · Cited by 425 · see citing works
An expanded tool kit for the auxin‐inducible degron system in budding yeast
Morawska, M., & Ulrich, H. D. (2013) · Yeast · doi:10.1002/yea.2967 · Cited by 414 · see citing works
3D Chromosome Regulatory Landscape of Human Pluripotent Cells
Ji, X., Dadon, D. B., Powell, B. E., Fan, Z. P., Borges-Rivera, D., Shachar, S., Weintraub, A. S., Hnisz, D., Pegoraro, G., Lee, T. I., et al. (2016) · Cell Stem Cell · doi:10.1016/j.stem.2015.11.007 · Cited by 400 · see citing works
Cohesin-mediated interactions organize chromosomal domain architecture
Sofueva, S., Yaffe, E., Chan, W., Georgopoulou, D., Vietri Rudan, M., Mira‐Bontenbal, H., Pollard, S. M., Schroth, G. P., Tanay, A., & Hadjur, S. (2013) · The EMBO Journal · doi:10.1038/emboj.2013.237 · Cited by 394 · see citing works
Position-effect protection and enhancer blocking by the chicken β-globin insulator are separable activities
Targa, F. R., Pikaart, M. J., Burgess-Beusse, B. L., Bell, A. C., Litt, M. D., West, A. G., Gaszner, M., & Felsenfeld, G. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.102179399 · Cited by 381 · see citing works
The Hitchhiker’s guide to Hi-C analysis: Practical guidelines
Lajoie, B. R., Dekker, J., & Kaplan, N. (2014) · Methods · doi:10.1016/j.ymeth.2014.10.031 · Cited by 377 · see citing works
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Structural and functional diversity of Topologically Associating Domains
Dekker, J., & Heard, É. (2015) · FEBS Letters · doi:10.1016/j.febslet.2015.08.044 · Cited by 313 · see citing works
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Distinct structural transitions of chromatin topological domains correlate with coordinated hormone-induced gene regulationPreprint
Dily, F. L., Baù, D., Pohl, A., Vicent, G. P., Serra, F., Soronellas, D., Castellano, G., Wright, R. H. G., Ballaré, C., Filion, G. J. P., et al. (2014) · Genes & Development · doi:10.1101/gad.241422.114 · Cited by 297 · see citing works
CTCF: making the right connectionsPreprint
Ghirlando, R., & Felsenfeld, G. (2016) · Genes & Development · doi:10.1101/gad.277863.116 · Cited by 292 · see citing works
High Resolution Genome Wide Binding Event Finding and Motif Discovery Reveals Transcription Factor Spatial Binding Constraints
Guo, Y., Mahony, S., & Gifford, D. K. (2012) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1002638 · Cited by 288 · see citing works
The Elg1 replication factor C-like complex functions in PCNA unloading during DNA replication
Kubota, T., Nishimura, K., Kanemaki, M. T., & Donaldson, A. D. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.02.012 · Cited by 279 · see citing works
An interactive environment for agile analysis and visualization of ChIP-sequencing data
Lerdrup, M., Johansen, J. V., Singh, S. A., & Hansen, K. H. (2016) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.3180 · Cited by 278 · see citing works
Genome-wide nucleosome positioning during embryonic stem cell development
Teif, V. B., Vainshtein, Y., Caudron-Herger, M., Mallm, J.-P., Marth, C., Höfer, T., & Rippe, K. (2012) · Nature Structural &Molecular Biology · doi:10.1038/nsmb.2419 · Cited by 260 · see citing works
The 4D nucleome: Evidence for a dynamic nuclear landscape based on co‐aligned active and inactive nuclear compartments
Cremer, T., Cremer, M., Hübner, B., Strickfaden, H., Smeets, D., Popken, J., Sterr, M., Markaki, Y., Rippe, K., & Cremer, C. (2015) · FEBS Letters · doi:10.1016/j.febslet.2015.05.037 · Cited by 246 · see citing works
Epigenetic Silencing of the p16 Tumor Suppressor Is Associated with Loss of CTCF Binding and a Chromatin Boundary
Witcher, M., & Emerson, B. M. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.04.001 · Cited by 235 · see citing works
Complex Interdependence Regulates Heterotypic Transcription Factor Distribution and Coordinates Cardiogenesis
Luna‐Zurita, L., Stirnimann, C. U., Glatt, S., Kaynak, B. L., Thomas, S., Baudin, F., Samee, M. A. H., He, D. X., Small, E. M., Mileikovsky, M., et al. (2016) · Cell · doi:10.1016/j.cell.2016.01.004 · Cited by 207 · see citing works
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Polymer physics of chromosome large-scale 3D organisation
Chiariello, A. M., Annunziatella, C., Bianco, S., Esposito, A., & Nicodemi, M. (2016) · Scientific Reports · doi:10.1038/srep29775 · Cited by 194 · see citing works
In search of the determinants of enhancer–promoter interaction specificity
van Arensbergen, J., van Steensel, B., & Bussemaker, H. J. (2014) · Trends in Cell Biology · doi:10.1016/j.tcb.2014.07.004 · Cited by 172 · see citing works
A Wt1-Controlled Chromatin Switching Mechanism Underpins Tissue-Specific Wnt4 Activation and Repression
Essafi, A., Webb, A., Berry, R. L., Slight, J., Burn, S. F., Spraggon, L., Velecela, V., Martínez-Estrada, O. M., Wiltshire, J. H., Roberts, S. G. E., et al. (2011) · Developmental Cell · doi:10.1016/j.devcel.2011.07.014 · Cited by 165 · see citing works
Different enhancer classes in Drosophila bind distinct architectural proteins and mediate unique chromatin interactions and 3D architecture
Cubeñas-Potts, C., Rowley, M. J., Lyu, X., Li, G., Lei, E. P., & Corces, V. G. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw1114 · Cited by 157 · see citing works
An improved Flp deleter mouse in C57Bl/6 based on Flpo recombinase
Kranz, A., Fu, J., Duerschke, K., Weidlich, S., Naumann, R., Stewart, A. F., & Anastassiadis, K. (2010) · genesis · doi:10.1002/dvg.20641 · Cited by 153 · see citing works
Stable Chromosome Condensation Revealed by Chromosome Conformation Capture
Eagen, K. P., Hartl, T. A., & Kornberg, R. D. (2015) · Cell · doi:10.1016/j.cell.2015.10.026 · Cited by 146 · see citing works
Maternal depletion of CTCF reveals multiple functions during oocyte and preimplantation embryo development
Wan, L., Pan, H., Hannenhalli, S. S., Cheng, Y., Ma, J., Fedoriw, A., Lobanenkov, V. V., Latham, K. E., Schultz, R. M., & Bartolomei, M. S. (2008) · Development · doi:10.1242/dev.024539 · Cited by 143 · see citing works
FISH-ing for captured contacts: towards reconciling FISH and 3C
Fudenberg, G., & Imakaev, M. (2017) · Nature Methods · doi:10.1038/nmeth.4329 · Cited by 141 · see citing works
Loss of Maternal CTCF Is Associated with Peri-Implantation Lethality of Ctcf Null Embryos
Moore, J. M., Rabaia, N. A., Smith, L. E., Fagerlie, S. R., Gurley, K. E., Loukinov, D., Distèche, C. M., Collins, S. J., Kemp, C. J., Lobanenkov, V. V., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0034915 · Cited by 133 · see citing works
Closing the loop: 3C versus DNA FISH
Giorgetti, L., & Heard, E. (2016) · Genome Biology · doi:10.1186/s13059-016-1081-2 · Cited by 131 · see citing works
Functional Analysis of CTCF During Mammalian Limb Development
Soshnikova, N. V., Montavon, T., Leleu, M., Galjart, N., & Duboule, D. (2010) · Developmental Cell · doi:10.1016/j.devcel.2010.11.009 · Cited by 130 · see citing works
USF1 Recruits Histone Modification Complexes and Is Critical for Maintenance of a Chromatin Barrier
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The Chromatin Remodelling Enzymes SNF2H and SNF2L Position Nucleosomes adjacent to CTCF and Other Transcription Factors
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Chromatin loops as allosteric modulators of enhancer-promoter interactions
Doyle, B., Fudenberg, G., Imakaev, M., & Mirny, L. A. (2014) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003867 · Cited by 114 · cited 1× · see citing works
“This observation supports at the genome-wide level the notion that CTCF can mediate enhancerblocking insulation through the specification of TAD boundaries, in line with previous locus-specific studies (Dowen et al., 2014; Doyle et al., 2014; Lupiáñez et al., 2015; Nora et al., 2012).”
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Features that define the best ChIP-seq peak calling algorithms
Thomas, R., Thomas, S., Holloway, A. K., & Pollard, K. S. (2016) · Briefings in Bioinformatics · doi:10.1093/bib/bbw035 · Cited by 112 · see citing works
Comparative analyses of CTCF and BORIS occupancies uncover two distinct classes of CTCF binding genomic regions
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Large-scale chromatin organization: the good, the surprising, and the still perplexing
Belmont, A. S. (2013) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2013.10.002 · Cited by 104 · see citing works
The male germ cell gene regulator CTCFL is functionally different from CTCF and binds CTCF-like consensus sites in a nucleosome composition-dependent manner
Sleutels, F., Soochit, W., Bartkuhn, M., Heath, H., Dienstbach, S., Bergmaier, P., Franke, V., Rosa-Garrido, M., van de Nobelen, S., Caesar, L., et al. (2012) · Epigenetics & Chromatin · doi:10.1186/1756-8935-5-8 · Cited by 96 · see citing works
My5C: web tools for chromosome conformation capture studies
Lajoie, B. R., van Berkum, N. L., Sanyal, A., & Dekker, J. (2009) · Nature Methods · doi:10.1038/nmeth1009-690 · Cited by 88 · see citing works
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An inducible and reversible mouse genetic rescue system
Zeng, H., Horie, K., Madisen, L., Pavlova, M. N., Gragerova, G., Rohde, A. D., Schimpf, B. A., Liang, Y., Ojala, E., Kramer, F., et al. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.1000069 · Cited by 87 · see citing works
Genome-wide assessment of sequence-intrinsic enhancer responsiveness at single-base-pair resolution
Arnold, C. D., Zabidi, M. M. A., Pagani, M., Rath, M., Schernhuber, K., Kazmar, T., & Stark, A. (2016) · Nature Biotechnology · doi:10.1038/nbt.3739 · Cited by 87 · see citing works
Dual Effect of CTCF Loss on Neuroprogenitor Differentiation and Survival
Watson, L. A., Wang, X., Elbert, A., Kernohan, K. D., Galjart, N., & Bérubé, N. G. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.3769-13.2014 · Cited by 81 · see citing works
Enhancer identification in mouse embryonic stem cells using integrative modeling of chromatin and genomic features
Chen, C., Morris, Q., & Mitchell, J. A. (2012) · BMC Genomics · doi:10.1186/1471-2164-13-152 · Cited by 70 · see citing works
Genome-Wide Localization of Protein-DNA Binding and Histone Modification by a Bayesian Change-Point Method with ChIP-seq Data
Xing, H., Mo, Y., Liao, W., & Zhang, M. Q. (2012) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1002613 · Cited by 67 · see citing works
A Discrete Transition Zone Organizes the Topological and Regulatory Autonomy of the Adjacent Tfap2c and Bmp7 Genes
Tsujimura, T., Klein, F. A., Langenfeld, K., Glaser, J., Huber, W. K., & Spitz, F. (2015) · PLoS Genetics · doi:10.1371/journal.pgen.1004897 · Cited by 64 · see citing works
Flanking HS-62.5 and 3′ HS1, and regions upstream of the LCR, are not required for β-globin transcription
Bender, M. A., Byron, R., Ragoczy, T., Telling, A., Bulger, M., & Groudine, M. (2006) · Blood · doi:10.1182/blood-2006-04-014431 · Cited by 59 · see citing works
Mapping the 3D genome: Aiming for consilience
Dekker, J. (2016) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.151 · Cited by 58 · see citing works
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Two independent modes of chromosome organization are revealed by cohesin removalPreprint
Schwarzer, W., Abdennur, N., Goloborodko, A., Pękowska, A., Fudenberg, G., Loe-Mie, Y., Fonseca, N. A., Huber, W., Haering, C., Mirny, L., et al. (2016) · bioRxiv · doi:10.1101/094185 · Cited by 39 · see citing works
Self-citation
A Genetic Approach to the Recruitment of PRC2 at the HoxD Locus
Schorderet, P., Lonfat, N., Darbellay, F., Tschopp, P., Gitto, S., Soshnikova, N. V., & Duboule, D. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003951 · Cited by 34 · see citing works
Distinct polymer physics principles govern chromatin dynamics in mouse and Drosophila topological domains
Ea, V., Sexton, T., Gostan, T., Herviou, L., Baudement, M.-O., Zhang, Y., Berlivet, S., Lelay-Taha, M.-N., Cathala, G., Lesne, A., et al. (2015) · BMC Genomics · doi:10.1186/s12864-015-1786-8 · Cited by 18 · see citing works
FISH-ing for captured contacts: towards reconciling FISH and 3CPreprint
Fudenberg, G., & Imakaev, M. V. (2016) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/081448 · Cited by 10 · see citing works
Experimental Strategies to Manipulate the Cellular Levels of the Multifunctional Factor CTCF
González-Buendía, E., Pérez‐Molina, R., Ayala-Ortega, E., Guerrero, G., & Targa, F. R. (2014) · Methods in molecular biology · doi:10.1007/978-1-4939-0856-1_5 · Cited by 6 · see citing works

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Cohesin Loss Eliminates All Loop Domains
Rao, S. S. P., Huang, S.-C., Glenn St Hilaire, B., Engreitz, J. M., Perez, E. M., Kieffer-Kwon, K.-R., Sanborn, A. L., Johnstone, S. E., Bascom, G. D., Bochkov, I. D., et al. (2017) · Cell · doi:10.1016/j.cell.2017.09.026 · Cited by 1,883 · see citing works
“Our data is consistent with a previous report that genome compartmentalization is preserved after depletion of cohesin (Seitan et al., 2013) or CTCF (Nora et al., 2017).”
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Multiscale 3D Genome Rewiring during Mouse Neural Development
Bonev, B., Mendelson Cohen, N., Szabo, Q., Fritsch, L., Papadopoulos, G. L., Lubling, Y., Xu, X., Lv, X., Hugnot, J.-P., Tanay, A., et al. (2017) · Cell · doi:10.1016/j.cell.2017.09.043 · Cited by 1,338 · see citing works
Organizational principles of 3D genome architecture
Rowley, M. J., & Corces, V. G. (2018) · Nature Reviews Genetics · doi:10.1038/s41576-018-0060-8 · Cited by 1,171 · see citing works
Two independent modes of chromatin organization revealed by cohesin removal
Schwarzer, W., Abdennur, N., Goloborodko, A., Pekowska, A., Fudenberg, G., Loe-Mie, Y., Fonseca, N. A., Huber, W., Haering, C. H., Mirny, L., et al. (2017) · Nature · doi:10.1038/nature24281 · Cited by 1,196 · see citing works
Self-citation
Long-range enhancer–promoter contacts in gene expression control
Schoenfelder, S., & Fraser, P. (2019) · Nature Reviews Genetics · doi:10.1038/s41576-019-0128-0 · Cited by 1,102 · see citing works
YY1 Is a Structural Regulator of Enhancer-Promoter Loops
Weintraub, A. S., Li, C. H., Zamudio, A. V., Sigova, A. A., Hannett, N. M., Day, D. S., Abraham, B. J., Cohen, M. A., Nabet, B., Buckley, D. L., et al. (2017) · Cell · doi:10.1016/j.cell.2017.11.008 · Cited by 992 · see citing works
“These results were comparable to the effects observed with the rescue of CTCF-CTCF interactions in a similar experiment described recently (Figures 7F and S7C) (Nora et al., 2017), and support the model that YY1 contributes to structuring of a large fraction of enhancer-promoter loops genome-wide.”
High-resolution TADs reveal DNA sequences underlying genome organization in flies
Ramírez, F., Bhardwaj, V., Arrigoni, L., Lam, K. C., Grüning, B. A., Villaveces, J. M., Habermann, B. H., Akhtar, A., & Manke, T. (2018) · Nature Communications · doi:10.1038/s41467-017-02525-w · Cited by 974 · see citing works
Topologically associating domains and chromatin loops depend on cohesin and are regulated by CTCF, WAPL, and PDS5 proteins
Wutz, G., Várnai, C., Nagasaka, K., Cisneros, D. A., Stocsits, R. R., Tang, W., Schoenfelder, S., Jessberger, G., Muhar, M., Hossain, M. J., et al. (2017) · The EMBO Journal · doi:10.15252/embj.201798004 · Cited by 864 · see citing works
A pathway for mitotic chromosome formation
Gibcus, J. H., Samejima, K., Goloborodko, A. A., Samejima, I., Naumova, N., Nuebler, J., Kanemaki, M. T., Xie, L., Paulson, J. R., Earnshaw, W. C., et al. (2018) · Science · doi:10.1126/science.aao6135 · Cited by 709 · see citing works
Self-citation
Structural variation in the 3D genome
Spielmann, M., Lupiáñez, D. G., & Mundlos, S. (2018) · Nature Reviews Genetics · doi:10.1038/s41576-018-0007-0 · Cited by 719 · see citing works
The role of 3D genome organization in development and cell differentiation
Zheng, H., & Xie, W. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0132-4 · Cited by 711 · see citing works
Resolving the 3D Landscape of Transcription-Linked Mammalian Chromatin Folding
Hsieh, T.-H. S., Cattoglio, C., Slobodyanyuk, E., Hansen, A. S., Rando, O. J., Tjian, R., & Darzacq, X. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.03.002 · Cited by 661 · see citing works
Developmental enhancers and chromosome topology
Furlong, E. E. M., & Levine, M. (2018) · Science · doi:10.1126/science.aau0320 · Cited by 641 · see citing works
Heterochromatin drives compartmentalization of inverted and conventional nuclei
Falk, M., Feodorova, Y., Naumova, N., Imakaev, M., Lajoie, B. R., Leonhardt, H., Joffe, B., Dekker, J., Fudenberg, G., Solovei, I., et al. (2019) · Nature · doi:10.1038/s41586-019-1275-3 · Cited by 646 · see citing works
Self-citation
Chromatin organization by an interplay of loop extrusion and compartmental segregation
Nuebler, J., Fudenberg, G., Imakaev, M., Abdennur, N. A., & Mirny, L. A. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1717730115 · Cited by 617 · see citing works
“Motivated by recent experiments that point toward such an interplay (12, 37), we used polymer models of chromosomes to investigate whether simultaneous action of loop extrusion and compartmental segregation can quantitatively reproduce experimental findings.”
MethodSelf-citation
Ultrastructural Details of Mammalian Chromosome Architecture
Krietenstein, N., Abraham, S., Venev, S. V., Abdennur, N., Gibcus, J., Hsieh, T.-H. S., Parsi, K. M., Yang, L., Maehr, R., Mirny, L. A., et al. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.03.003 · Cited by 622 · see citing works
Self-citation
CTCF and cohesin regulate chromatin loop stability with distinct dynamics
Hansen, A. S., Pustova, I., Cattoglio, C., Tjian, R., & Darzacq, X. (2017) · eLife · doi:10.7554/elife.25776 · Cited by 613 · see citing works
Principles of genome folding into topologically associating domains
Szabo, Q., Bantignies, F., & Cavalli, G. (2019) · Science Advances · doi:10.1126/sciadv.aaw1668 · Cited by 594 · see citing works
The Energetics and Physiological Impact of Cohesin Extrusion
Vian, L., Pękowska, A., Rao, S. S. P., Kieffer-Kwon, K.-R., Jung, S., Baranello, L., Huang, S.-C., El Khattabi, L., Dose, M., Pruett, N., et al. (2018) · Cell · doi:10.1016/j.cell.2018.03.072 · Cited by 581 · see citing works
Evolutionarily Conserved Principles Predict 3D Chromatin Organization
Rowley, M. J., Nichols, M. H., Lyu, X., Ando‐Kuri, M., Rivera, S., Hermetz, K. E., Wang, P., Ruan, Y., & Corces, V. G. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.07.022 · Cited by 535 · see citing works
“Recently published studies have examined the role of CTCF in the formation of loops and TADs using an auxin-mediated degradation system in mammals (Kubo et al., 2017; Nora et al., 2017).”
The auxin-inducible degron 2 technology provides sharp degradation control in yeast, mammalian cells, and mice
Yesbolatova, A., Saito, Y., Kitamoto, N., Makino‐Itou, H., Ajima, R., Nakano, R., Nakaoka, H., Fukui, K., Gamo, K., Tominari, Y., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19532-z · Cited by 513 · see citing works
Transcription factors and 3D genome conformation in cell-fate decisions
Stadhouders, R., Filion, G. J. P., & Graf, T. (2019) · Nature · doi:10.1038/s41586-019-1182-7 · Cited by 519 · see citing works
Genome folding through loop extrusion by SMC complexes
Davidson, I. F., & Peters, J. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00349-7 · Cited by 507 · see citing works
The structural basis for cohesin–CTCF-anchored loops
Li, Y., Haarhuis, J. H. I., Sedeño Cacciatore, Á., Oldenkamp, R., van Ruiten, M. S., Willems, L., Teunissen, H., Muir, K. W., de Wit, E., Rowland, B. D., et al. (2020) · Nature · doi:10.1038/s41586-019-1910-z · Cited by 459 · see citing works
Dynamics of CTCF- and cohesin-mediated chromatin looping revealed by live-cell imaging
Gabriele, M., Brandão, H. B., Grosse-Holz, S., Jha, A., Dailey, G. M., Cattoglio, C., Hsieh, T.-H. S., Mirny, L., Zechner, C., & Hansen, A. S. (2022) · Science · doi:10.1126/science.abn6583 · Cited by 506 · see citing works
Self-citation
Chemically induced proximity in biology and medicine
Stanton, B. Z., Chory, E. J., & Crabtree, G. R. (2018) · Science · doi:10.1126/science.aao5902 · Cited by 475 · see citing works
“Recently, auxin-mediated degradation of the transcription factor CTCF (60) has differentiated its roles in local topologically associating domain (TAD) structure from chromosomal-compartment architecture.”
Background
Roles of transposable elements in the regulation of mammalian transcription
Fueyo, R., Judd, J., Feschotte, C., & Wysocka, J. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-022-00457-y · Cited by 451 · see citing works
Transcription Elongation Can Affect Genome 3D Structure
Heinz, S., Texari, L., Hayes, M. G. B., Urbanowski, M., Chang, M. W., Givarkes, N., Rialdi, A., White, K. M., Albrecht, R. A., Pache, L., et al. (2018) · Cell · doi:10.1016/j.cell.2018.07.047 · Cited by 453 · see citing works
Extensive Heterogeneity and Intrinsic Variation in Spatial Genome Organization
Finn, E. H., Pegoraro, G., Brandão, H. B., Valton, A.-L., Oomen, M. E., Dekker, J., Mirny, L., & Misteli, T. (2019) · Cell · doi:10.1016/j.cell.2019.01.020 · Cited by 459 · see citing works
Self-citation
Nonlinear control of transcription through enhancer–promoter interactions
Zuin, J., Roth, G., Zhan, Y., Cramard, J., Redolfi, J., Piskadlo, E., Mach, P., Kryzhanovska, M., Tihanyi, G., Kohler, H., et al. (2022) · Nature · doi:10.1038/s41586-022-04570-y · Cited by 415 · see citing works
Enhancer–promoter interactions and transcription are largely maintained upon acute loss of CTCF, cohesin, WAPL or YY1
Hsieh, T.-H. S., Cattoglio, C., Slobodyanyuk, E., Hansen, A. S., Darzacq, X., & Tjian, R. (2022) · Nature Genetics · doi:10.1038/s41588-022-01223-8 · Cited by 406 · see citing works
Towards a comprehensive catalogue of validated and target-linked human enhancers
Gasperini, M., Tome, J. M., & Shendure, J. (2020) · Nature Reviews Genetics · doi:10.1038/s41576-019-0209-0 · Cited by 396 · see citing works
Understanding 3D genome organization by multidisciplinary methods
Jerković, I., & Cavalli, G. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00362-w · Cited by 389 · see citing works
A mechanism of cohesin‐dependent loop extrusion organizes zygotic genome architecture
Gassler, J., Brandão, H. B., Imakaev, M., Flyamer, I. M., Ladstätter, S., Bickmore, W. A., Peters, J., Mirny, L. A., & Tachibana, K.-E. K. (2017) · The EMBO Journal · doi:10.15252/embj.201798083 · Cited by 363 · see citing works
“…cohesin colocalizes with CTCF and is associated with TADs and chromatin loops (Wendt et al , 2008; Dixon et al , 2012; Nora et al , 2012; Phillips-Cremins et al , 2013; Rao et al , 2014; Hansen et al , 2017; Nora et al , 2017), which implicated cohesin as a regulator of intra-chromosomal structure.”
BackgroundMethodInfluentialSelf-citation
Transcriptionally active HERV-H retrotransposons demarcate topologically associating domains in human pluripotent stem cells
Zhang, Y., Li, T., Preißl, S., Amaral, M. L., Grinstein, J. D., Farah, E. N., Destici, E., Qiu, Y., Hu, R., Lee, A. Y., et al. (2019) · Nature Genetics · doi:10.1038/s41588-019-0479-7 · Cited by 367 · see citing works
Live-cell imaging reveals enhancer-dependent Sox2 transcription in the absence of enhancer proximity
Alexander, J. M., Guan, J., Li, B., Maliskova, L., Song, M., Shen, Y., Huang, B., Lomvardas, S., & Weiner, O. D. (2019) · eLife · doi:10.7554/elife.41769 · Cited by 346 · see citing works
On the existence and functionality of topologically associating domains
Beagan, J. A., & Phillips‐Cremins, J. E. (2020) · Nature Genetics · doi:10.1038/s41588-019-0561-1 · Cited by 357 · see citing works
Transcription factors orchestrate dynamic interplay between genome topology and gene regulation during cell reprogramming
Stadhouders, R., Vidal, E., Serra, F., Stefano, B. D., Dily, F. L., Quilez, J., Gómez, A., Collombet, S., Berenguer, C., Cuartero, Y., et al. (2018) · Nature Genetics · doi:10.1038/s41588-017-0030-7 · Cited by 352 · see citing works
Highly rearranged chromosomes reveal uncoupling between genome topology and gene expression
Ghavi-Helm, Y., Jankowski, A., Meiers, S., Viales, R. R., Korbel, J. O., & Furlong, E. E. M. (2019) · Nature Genetics · doi:10.1038/s41588-019-0462-3 · Cited by 354 · see citing works
Organization of Chromosomal DNA by SMC Complexes
Yatskevich, S., Rhodes, J., & Nasmyth, K. (2019) · Annual Review of Genetics · doi:10.1146/annurev-genet-112618-043633 · Cited by 337 · see citing works
Simultaneous profiling of 3D genome structure and DNA methylation in single human cells
Lee, D.-S., Luo, C., Zhou, J., Chandran, S., Rivkin, A., Bartlett, A., Nery, J. R., Fitzpatrick, C., O’Connor, C., Dixon, J. R., et al. (2019) · Nature Methods · doi:10.1038/s41592-019-0547-z · Cited by 340 · see citing works
3D Chromatin Architecture of Large Plant Genomes Determined by Local A/B Compartments
Dong, P., Tu, X., Chu, P.-Y., Lü, P., Zhu, N., Grierson, D. S., Du, B., Li, P., & Zhong, S. (2017) · Molecular Plant · doi:10.1016/j.molp.2017.11.005 · Cited by 315 · see citing works
The relationship between genome structure and function
Oudelaar, A. M., & Higgs, D. R. (2021) · Nature Reviews Genetics · doi:10.1038/s41576-020-00303-x · Cited by 304 · see citing works
The epigenetic basis of cellular heterogeneity
Carter, B. C., & Zhao, K. (2020) · Nature Reviews Genetics · doi:10.1038/s41576-020-00300-0 · Cited by 314 · see citing works
Static and Dynamic DNA Loops form AP-1-Bound Activation Hubs during Macrophage Development
Phanstiel, D. H., Van Bortle, K., Spacek, D., Hess, G. T., Shamim, M. S., Machol, I., Love, M. I., Aiden, E. L., Bassik, M. C., & Snyder, M. P. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.08.006 · Cited by 299 · see citing works
Functional dissection of the Sox9–Kcnj2 locus identifies nonessential and instructive roles of TAD architecture
Despang, A., Schöpflin, R., Franke, M., Ali, S., Jerković, I., Paliou, C., Chan, W.-L., Timmermann, B., Wittler, L., Vingron, M., et al. (2019) · Nature Genetics · doi:10.1038/s41588-019-0466-z · Cited by 306 · see citing works
Promoter-proximal CTCF binding promotes distal enhancer-dependent gene activation
Kubo, N., Ishii, H., Xiong, X., Bianco, S., Meitinger, F., Hu, R., Hocker, J. D., Conte, M., Gorkin, D., Yu, M., et al. (2021) · Nature Structural & Molecular Biology · doi:10.1038/s41594-020-00539-5 · Cited by 289 · see citing works
Emerging Evidence of Chromosome Folding by Loop ExtrusionPreprint
Fudenberg, G., Abdennur, N. A., Imakaev, M., Goloborodko, A. A., & Mirny, L. A. (2017) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2017.82.034710 · Cited by 287 · see citing works
“For CTCF, cells begin dying after about 4 days of stringent depletion (Nora et al. 2017).”
BackgroundMethodInfluentialSelf-citation
Control of DNA replication timing in the 3D genome
Marchal, C., Sima, J., & Gilbert, D. M. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0162-y · Cited by 287 · see citing works
Predicting 3D genome folding from DNA sequence with Akita
Fudenberg, G., Kelley, D. R., & Pollard, K. S. (2020) · Nature Methods · doi:10.1038/s41592-020-0958-x · Cited by 292 · see citing works
Deciphering the multi-scale, quantitative cis-regulatory code
Kim, S., & Wysocka, J. (2023) · Molecular Cell · doi:10.1016/j.molcel.2022.12.032 · Cited by 282 · see citing works
Early metazoan cell type diversity and the evolution of multicellular gene regulation
Sebé-Pedrós, A., Chomsky, E., Pang, K., Lara‐Astiaso, D., Gaiti, F., Mukamel, Z., Amit, I., Hejnol, A., Degnan, B. M., & Tanay, A. (2018) · Nature Ecology & Evolution · doi:10.1038/s41559-018-0575-6 · Cited by 292 · see citing works
TADs are 3D structural units of higher-order chromosome organization in Drosophila
Szabo, Q., Jost, D., Chang, J., Cattoni, D. I., Papadopoulos, G. L., Bonev, B., Sexton, T., Gurgo, J., Jacquier, C., Nöllmann, M., et al. (2018) · Science Advances · doi:10.1126/sciadv.aar8082 · Cited by 275 · see citing works
Beyond the RNA-dependent function of LncRNA genes
Ali, T., & Grote, P. (2020) · eLife · doi:10.7554/elife.60583 · Cited by 281 · see citing works
Distinct Classes of Chromatin Loops Revealed by Deletion of an RNA-Binding Region in CTCF
Hansen, A. S., Hsieh, T.-H. S., Cattoglio, C., Pustova, I., Saldaña-Meyer, R., Reinberg, D., Darzacq, X., & Tjian, R. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.07.039 · Cited by 279 · see citing works
RNA Interactions Are Essential for CTCF-Mediated Genome Organization
Saldaña-Meyer, R., Rodriguez-Hernaez, J., Escobar, T. M., Nishana, M., Jácome-López, K., Nora, E. P., Bruneau, B. G., Tsirigos, A., Furlan-Magaril, M., Skok, J. A., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.08.015 · Cited by 278 · see citing works
“We then sorted the successfully infected cells (mCherry positive and GFP negative; Figure 2B) to obtain a pooled population of steady-state rescues after degradation of the endogenous CTCF protein via AID (Figures 2B and S2A).”
BackgroundMethodResultInfluentialSelf-citation
Recent evidence that TADs and chromatin loops are dynamic structures
Hansen, A. S., Cattoglio, C., Darzacq, X., & Tjian, R. (2018) · Nucleus · doi:10.1080/19491034.2017.1389365 · Cited by 266 · see citing works
Cohesin and CTCF control the dynamics of chromosome folding
Mach, P., Kos, P. I., Zhan, Y., Cramard, J., Gaudin, S., Tünnermann, J., Marchi, E., Eglinger, J., Zuin, J., Kryzhanovska, M., et al. (2022) · Nature Genetics · doi:10.1038/s41588-022-01232-7 · Cited by 269 · see citing works
Self-citation
Intrinsic Dynamics of a Human Gene Reveal the Basis of Expression Heterogeneity
Rodriguez, J., Ren, G., Day, C. R., Zhao, K., Chow, C. C., & Larson, D. R. (2018) · Cell · doi:10.1016/j.cell.2018.11.026 · Cited by 267 · see citing works
Mammalian ISWI and SWI/SNF selectively mediate binding of distinct transcription factors
Barišić, D., Stadler, M. B., Iurlaro, M., & Schübeler, D. (2019) · Nature · doi:10.1038/s41586-019-1115-5 · Cited by 265 · see citing works
Region Capture Micro-C reveals coalescence of enhancers and promoters into nested microcompartments
Goel, V. Y., Huseyin, M. K., & Hansen, A. S. (2023) · Nature Genetics · doi:10.1038/s41588-023-01391-1 · Cited by 271 · see citing works
CTCF-Mediated Enhancer-Promoter Interaction Is a Critical Regulator of Cell-to-Cell Variation of Gene Expression
Ren, G., Jin, W., Cui, K., Rodrigez, J., Hu, G., Zhang, Z., Larson, D. R., & Zhao, K. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.08.026 · Cited by 255 · see citing works
“Our study provides an alternative explanation for those recent findings that targeted degradation of CTCF and/or Cohesin have very mild effect on the overall transcriptional changes (Nora et al., 2017).”
The role of transcription in shaping the spatial organization of the genome
van Steensel, B., & Furlong, E. E. M. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0114-6 · Cited by 247 · see citing works
Systematic evaluation of chromosome conformation capture assays
Oksuz, B. A., Yang, L., Abraham, S., Venev, S. V., Krietenstein, N., Parsi, K. M., Özadam, H., Oomen, M. E., Nand, A., Mao, H. Z., et al. (2021) · Nature Methods · doi:10.1038/s41592-021-01248-7 · Cited by 243 · see citing works
“For NAtuRE MEtHODS | www.nature.com/naturemethods HeLa libraries we excluded the chromosomes with translocations and used only chromosomes 4, 14, 17, 18, 20 and 21.”
Self-citation
X-Chromosome Inactivation: A Crossroads Between Chromosome Architecture and Gene Regulation
Galupa, R., & Heard, É. (2018) · Annual Review of Genetics · doi:10.1146/annurev-genet-120116-024611 · Cited by 246 · see citing works
Lamins Organize the Global Three-Dimensional Genome from the Nuclear Periphery
Zheng, X., Hu, J., Yue, S., Kristiani, L., Kim, M., Sauria, M. E. G., Taylor, J., Kim, Y., & Zheng, Y. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.05.017 · Cited by 238 · see citing works
Transcriptional Dysregulation of MYC Reveals Common Enhancer-Docking Mechanism
Schuijers, J., Manteiga, J. C., Weintraub, A. S., Day, D. S., Zamudio, A. V., Hnisz, D., Lee, T. I., & Young, R. A. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.03.056 · Cited by 232 · see citing works
“CTCF Enhancer-Docking Sites at Additional Genes Previous genomic studies have noted that CTCF might engender enhancer-promoter interactions at a minority of genes (Banani et al., 2017; Nora et al., 2017; Splinter et al., 2006; Zuin et al., 2014).”
BackgroundInfluential
Transcription shapes 3D chromatin organization by interacting with loop extrusion
Banigan, E. J., Tang, W., van den Berg, A. A., Stocsits, R. R., Wutz, G., Brandão, H. B., Busslinger, G. A., Peters, J., & Mirny, L. A. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2210480120 · Cited by 216 · see citing works
“However, while boundaries such as CTCF sites are stationary (Busslinger et al., 2017; Fudenberg et al., 2016; Nora et al., 2017; Sanborn et al., 2015; Wutz et al., 2017), RNAPs are mobile and can be dynamically controlled by transcriptional regulators.”
BackgroundSelf-citation
Two major mechanisms of chromosome organization
Mirny, L. A., Imakaev, M., & Abdennur, N. A. (2019) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2019.05.001 · Cited by 222 · see citing works
“Moreover, such affinity-based models cannot explain the experimentally observed fusion of neighboring TADs upon loss of CTCF or engineered deletion of CTCF sites [14,34,41,42].”
BackgroundMethodInfluentialSelf-citation
Polymer physics predicts the effects of structural variants on chromatin architecture
Bianco, S., Lupiáñez, D. G., Chiariello, A. M., Annunziatella, C., Kraft, K., Schöpflin, R., Wittler, L., Andrey, G., Vingron, M., Pombo, A., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0098-8 · Cited by 215 · see citing works
Evaluating Enhancer Function and Transcription
Field, A. R., & Adelman, K. (2020) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-011420-095916 · Cited by 218 · see citing works
“Unlike compartment structure, however, TAD structure is largely invariant across cell types (76, 137), rendering these domains insufficient to explain the highly dynamic nature of enhancer activity in different cell states.”
Background
Three-dimensional chromatin landscapes in T cell acute lymphoblastic leukemia
Kloetgen, A., Thandapani, P., Ntziachristos, P., Ghebrechristos, Y. E., Nomikou, S., Lazaris, C., Chen, X., Hu, H., Bakogianni, S., Wang, J., et al. (2020) · Nature Genetics · doi:10.1038/s41588-020-0602-9 · Cited by 219 · see citing works
Homotypic clustering of L1 and B1/Alu repeats compartmentalizes the 3D genome
Lu, J. Y., Chang, L., Li, T., Wang, T., Yin, Y., Zhan, G., Han, X., Zhang, K., Tao, Y., Percharde, M., et al. (2021) · Cell Research · doi:10.1038/s41422-020-00466-6 · Cited by 205 · see citing works
“S10b–i), which is consistent with the Hi-C results reported previously.(22,23,95)”
Result
Control of inducible gene expression links cohesin to hematopoietic progenitor self-renewal and differentiation
Cuartero, S., Weiss, F. D., Dharmalingam, G., Guo, Y., Ing-Simmons, E., Masella, S., Robles-Rebollo, I., Xiao, X., Wang, Y.-F., Barozzi, I., et al. (2018) · Nature Immunology · doi:10.1038/s41590-018-0184-1 · Cited by 210 · see citing works
CTCF mediates chromatin looping via N-terminal domain-dependent cohesin retention
Pugacheva, E. M., Kubo, N., Loukinov, D. I., Tajmul, M., Kang, S., Kovalchuk, A. L., Strunnikov, A. V., Zentner, G. E., Ren, B., & Lobanenkov, V. V. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1911708117 · Cited by 215 · see citing works
“These data are wholly consistent with the results from the previous studies using CTCF auxininducible degron system and with CTCF knockout mouse fibroblasts where, in the absence of CTCF, cohesin is no longer able to occupy CTCF binding sites (30, 31).”
Result
Coolpup.py: versatile pile-up analysis of Hi-C data
Flyamer, I. M., Illingworth, R. S., & Bickmore, W. A. (2020) · Bioinformatics · doi:10.1093/bioinformatics/btaa073 · Cited by 212 · see citing works
Large-Scale Topological Changes Restrain Malignant Progression in Colorectal Cancer
Johnstone, S. E., Reyes, A., Qi, Y., Adriaens, C., Hegazi, E., Pelka, K., Chen, J. H., Zou, L. S., Drier, Y., Hecht, V. C., et al. (2020) · Cell · doi:10.1016/j.cell.2020.07.030 · Cited by 215 · see citing works
Molecular basis of CTCF binding polarity in genome folding
Nora, E. P., Caccianini, L., Fudenberg, G., So, K., Kameswaran, V., Nagle, A., Uebersohn, A., Hajj, B., Saux, A. L., Coulon, A., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19283-x · Cited by 206 · see citing works
Self-citation
Assessing sufficiency and necessity of enhancer activities for gene expression and the mechanisms of transcription activationPreprint
Catarino, R. R., & Stark, A. (2018) · Genes & Development · doi:10.1101/gad.310367.117 · Cited by 205 · see citing works
“Indeed, depletion of CTCF or cohesin disrupts TADs and seems to instead favor contacts within active or respressive compartments (Hou et al. 2012; Seitan et al. 2013; Zuin et al. 2014; Ing-Simmons et al. 2015; Ulianov et al. 2016; Haarhuis et al. 2017; Nora et al. 2017; Rao et al. 2017; Schwarzer et al. 2017; Wutz et…”
Background
A chromosome folding intermediate at the condensin-to-cohesin transition during telophase
Abramo, K., Valton, A.-L., Venev, S. V., Özadam, H., Fox, A. N., & Dekker, J. (2019) · Nature Cell Biology · doi:10.1038/s41556-019-0406-2 · Cited by 196 · see citing works
“This temporal difference between TAD and loop formation, as compared to long-range inter-compartment interaction formation, might be related to the fact that these structures are formed by different mechanisms 14-16 .”
BackgroundMethodSelf-citation
Chromosome Conformation Capture and Beyond: Toward an Integrative View of Chromosome Structure and Function
McCord, R. P., Kaplan, N., & Giorgetti, L. (2020) · Molecular Cell · doi:10.1016/j.molcel.2019.12.021 · Cited by 204 · see citing works
“Global perturbations such as depletion of CTCF and cohesin have suggested that overall, the ‘significant’ structures associated to CTCF/cohesin are important for long range gene regulation of at least a subset of genes (Rao et al. 2017; Schwarzer et al. 2017; Nora et al. 2017).”
Background
Mechanisms of Interplay between Transcription Factors and the 3D Genome
Kim, S., & Shendure, J. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.08.010 · Cited by 204 · see citing works
Myc Regulates Chromatin Decompaction and Nuclear Architecture during B Cell Activation
Kieffer-Kwon, K.-R., Nimura, K., Rao, S. S. P., Xu, J., Jung, S., Pękowska, A., Dose, M., Stevens, E., Mathé, E. A., Dong, P., et al. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.07.013 · Cited by 204 · see citing works
“Furthermore, loops and loop domains vanish from the genome when CTCF is conditionally deleted (Nora et al., 2017).”
Landscape of cohesin-mediated chromatin loops in the human genome
Grubert, F., Srivas, R., Spacek, D. V., Kasowski, M. M., Ruiz-Velasco, M., Sinnott-Armstrong, N., Greenside, P., Narasimha, A. M., Liu, Q., Geller, B. S., et al. (2020) · Nature · doi:10.1038/s41586-020-2151-x · Cited by 201 · see citing works
Regulatory Landscaping: How Enhancer-Promoter Communication Is Sculpted in 3D
Robson, M. I., Ringel, A. R., & Mundlos, S. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.05.032 · Cited by 188 · see citing works
Regulation of single-cell genome organization into TADs and chromatin nanodomains
Szabo, Q., Donjon, A., Jerković, I., Papadopoulos, G. L., Cheutin, T., Bonev, B., Nora, E. P., Bruneau, B. G., Bantignies, F., & Cavalli, G. (2020) · Nature Genetics · doi:10.1038/s41588-020-00716-8 · Cited by 184 · see citing works
“5c), in agreement with the previously reported 2-to 3-fold decrease of CTCF level in untreated CTCF-AID compared to wild-type cells 11 .”
Self-citation
An efficient auxin-inducible degron system with low basal degradation in human cells
Li, S., Prasanna, X., Salo, V. T., Vattulainen, I., & Ikonen, E. (2019) · Nature Methods · doi:10.1038/s41592-019-0512-x · Cited by 176 · see citing works
CTCF is a DNA-tension-dependent barrier to cohesin-mediated loop extrusion
Davidson, I. F., Barth, R., Zaczek, M., van der Torre, J., Tang, W., Nagasaka, K., Janissen, R., Kerssemakers, J. W. J., Wutz, G., Dekker, C., et al. (2023) · Nature · doi:10.1038/s41586-023-05961-5 · Cited by 190 · see citing works
Enhancer selectivity in space and time: from enhancer–promoter interactions to promoter activation
Yang, J. H., & Hansen, A. S. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00710-6 · Cited by 191 · see citing works
The HoxD cluster is a dynamic and resilient TAD boundary controlling the segregation of antagonistic regulatory landscapesPreprint
Rodríguez-Carballo, E., Lopez‐Delisle, L., Zhan, Y., Fabre, P. J., Beccari, L. L., El-Idrissi, I., Huynh, T. H. N., Özadam, H., Dekker, J., & Duboule, D. (2017) · Genes & Development · doi:10.1101/gad.307769.117 · Cited by 174 · see citing works
“This may also explain why this boundary is still clearly detected in the almost complete absence of CTCF (data in (Nora et al. 2017)) Attracting landscapes, tolerated interactions and border directionality In several partial deletion alleles, ectopic interactions leaked over the border, leading to…”
BackgroundSelf-citation
Key role for CTCF in establishing chromatin structure in human embryos
Chen, X., Ke, Y., Wu, K., Zhao, H., Sun, Y., Gao, L., Liu, Z., Zhang, J., Tao, W., Hou, Z., et al. (2019) · Nature · doi:10.1038/s41586-019-1812-0 · Cited by 182 · see citing works
Cohesin Disrupts Polycomb-Dependent Chromosome Interactions in Embryonic Stem Cells
Rhodes, J. D. P., Feldmann, A., Hernández-Rodríguez, B., Díaz, N., Brown, J. M., Fursova, N. A., Blackledge, N. P., Prathapan, P., Dobrinic, P., Huseyin, M. K., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2019.12.057 · Cited by 187 · see citing works
“Cohesin Counteracts Polycomb Chromatin Domain Interactions Independently of CTCF and Insulation (A) A schematic illustrating the genotype of the CTCF-AID-GFP cell line (Nora et al., 2017).”
BackgroundMethodInfluential
CTCF mediates dosage- and sequence-context-dependent transcriptional insulation by forming local chromatin domains
Huang, H., Zhu, Q., Jussila, A., Han, Y., Bintu, B., Kern, C., Conte, M., Zhang, Y., Bianco, S., Chiariello, A. M., et al. (2021) · Nature Genetics · doi:10.1038/s41588-021-00863-6 · Cited by 187 · see citing works
Identifying cis Elements for Spatiotemporal Control of Mammalian DNA Replication
Sima, J., Chakraborty, A., Dileep, V., Michalski, M., Klein, K. N., Holcomb, N. P., Turner, J. L., Paulsen, M. T., Rivera‐Mulia, J. C., Trevilla‐García, C., et al. (2018) · Cell · doi:10.1016/j.cell.2018.11.036 · Cited by 179 · see citing works
“The Dppa2/4 domain corresponds to a TAD whose boundaries contain CTCF and cohesin binding sites (Nora et al., 2017; Yue et al., 2014; Dowen et al., 2014; Mumbach et al., 2016) and also align with compartment boundaries (Bonev et al., 2017).”
InfluentialSelf-citation
Harnessing the Power of Proteolysis for Targeted Protein Inactivation
Verma, R., Mohl, D., & Deshaies, R. J. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.01.010 · Cited by 185 · see citing works
Preformed chromatin topology assists transcriptional robustness of <i>Shh</i> during limb development
Paliou, C., Guckelberger, P., Schöpflin, R., Heinrich, V., Esposito, A., Chiariello, A. M., Bianco, S., Annunziatella, C., Helmuth, J., Haas, S., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1900672116 · Cited by 163 · see citing works
“Finally, our data suggest that the modest transcriptional alterations upon global CTCF/Cohesin depletion in nondifferentiating cells can be crucial to the process of differentiation and morphogenesis (7, 8, 10).”
Background
ESCO1 and CTCF enable formation of long chromatin loops by protecting cohesinSTAG1 from WAPL
Wutz, G., Ladurner, R., Hilaire, B. G. S., Stocsits, R. R., Nagasaka, K., Pignard, B., Sanborn, A. L., Tang, W., Várnai, C., Ivanov, M. P., et al. (2020) · eLife · doi:10.7554/elife.52091 · Cited by 167 · see citing works
“Consistent with previous results obtained by AID of CTCF (Nora et al., 2017; Wutz et al., 2017), depletion of CTCF by RNAi resulted in a reduction in the number of detectable loops (Figure 7A,C and D), and a decrease in the TAD insulation score (Figure 7E) but did not abolish long-range chromatin interactions.”
Result
Distinct roles of cohesin-SA1 and cohesin-SA2 in 3D chromosome organization
Kojic, A., Cuadrado, A., Koninck, M. D., Giménez-Llorente, D., Rodríguez-Corsino, M., Goméz-López, G., Dily, F. L., Martı́-Renom, M. A., & Losada, A. (2018) · Nature Structural & Molecular Biology · doi:10.1038/s41594-018-0070-4 · Cited by 169 · see citing works
“Recent studies depleting cohesin or CTCF in different cellular systems have led to the conclusion that TADs and compartments arise independently (21, 22).”
BackgroundResult
Cohesin-Dependent and -Independent Mechanisms Mediate Chromosomal Contacts between Promoters and Enhancers
Thiecke, M. J., Wutz, G., Muhar, M., Tang, W., Bevan, S., Malysheva, V., Stocsits, R., Neumann, T., Zuber, J., Fraser, P., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107929 · Cited by 177 · see citing works
SMCHD1 Merges Chromosome Compartments and Assists Formation of Super-Structures on the Inactive X
Wang, C., Jégu, T., Chu, H.-P. C., Oh, H. J., & Lee, J. T. (2018) · Cell · doi:10.1016/j.cell.2018.05.007 · Cited by 170 · see citing works

Targeted degradation of CTCF decouples local insulation of chromosome domains from higher-order genomic compartmentalization
(2016) · doi:10.1101/095802 · Cited by 17 · see citing works
Self-citation
Targeted degradation of CTCF decouples local insulation of chromosome domains from higher-order genomic compartmentalization [preprint]
Nora, E. P., Goloborodko, A. A., Valton, A.-L., Gibcus, J. H., Uebersohn, A., Abdennur, N. A., Dekker, J., Mirny, L. A., & Bruneau, B. (2017) · The Journal of the American Medical Association (JAMA) Network (American Medical Association)
Self-citation
Preservation of Chromatin Organization after Acute Loss of CTCF in Mouse Embryonic Stem CellsPreprint
Kubo, N., Ishii, H., Gorkin, D. U., Meitinger, F., Xiong, X., Fang, R., Liu, T., Ye, Z., Li, B., Dixon, J. R., et al. (2017) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/118737 · Cited by 48 · see citing works
Loop stacking organizes genome folding from TADs to chromosomes
Hafner, A., Park, M., Berger, S. E., Murphy, S. E., Nora, E. P., & Boettiger, A. N. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.04.008 · Cited by 120 · see citing works
Self-citation
Transcription factor CTCF and mammalian genome organization
Kotova, E. S., Акопов, С. Б., Sverdlov, E. D., & Николаев, Л. Г. (2014) · Biopolymers and Cell · doi:10.7124/bc.00089f · Cited by 2 · see citing works

Authors: Nora, E. P., Goloborodko, A., Valton, A.-L., Gibcus, J. H., Uebersohn, A., Abdennur, N., Dekker, J., Mirny, L. A., & Bruneau, B. G.
Affiliations: Gladstone Institutes (US)
Massachusetts Institute of Technology (US)
Howard Hughes Medical Institute (US)
Corresponding author: Nora, Elphège P.
Bruneau, Benoit G.
ORCID: Nora, Elphège P.
Goloborodko, Anton
Valton, Anne-Laure
Gibcus, Johan H.
Uebersohn, Alec
Abdennur, Nezar
Dekker, Job
Mirny, Leonid A.
Bruneau, Benoit G.
Venue: Cell
Publisher: Elsevier BV
Published: 2017-05
Volume: 169
Issue: 5
Pages: 930-944.e22
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2017.05.004
PMC: PMC5538188
OpenAlex: W2614144400
Semantic Scholar: e8afa0f77d39684b99c6679f6d08fd74cf1d90f5
Cited by: 1,709
References: 100
Citations by year: 2026: 146 · 2025: 162 · 2024: 172 · 2023: 187 · 2022: 204 · 2021: 231 · 2020: 207 · 2019: 196 · 2018: 139 · 2017: 63 · 2012: 1
FWCI: 67.99
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 382 d)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
eScholarship (California Digital Library) (submittedVersion)
The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
HAL (submittedVersion)
Funders: EMBO (ALTF523-2013)
HSFP
NIH/National Heart, Lung, and Blood Institute
Bench to Bassinet Program (U01HL098179)
Gladstone Institutes
William H. Younger, Jr
UCSF-Gladstone Institute of Virology & Immunology Center for AIDS Research (NIH P30 AI027763)
National Human Genome Research Institute (R01 HG003143, U54 HG007010)
NIH Common Fund (U54 DK107980, U01 DA 040588)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
Keywords: CTCF, topologically associating domains, chromatin insulation, chromosome folding, 3D genome organization, enhancer blocking, heterochromatin spreading, auxin-inducible degron, mouse embryonic stem cells, chromatin looping
MeSH terms: CCCTC-Binding Factor, Animals, Cell Cycle, Chromatin, Gene Expression Regulation, Indoleacetic Acids, Repressor Proteins, Transcription, Genetic, Chromosomes, Mammalian, Mice, Embryonic Stem Cells

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Targeted Degradation of CTCF Decouples Local Insulation of Chromosome Domains from Genomic Compartmentalization

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