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Targeted Degradation of CTCF Decouples Local Insulation of Chromosome Domains from Genomic Compartmentalization
Open accessPublished version of a preprint
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.
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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.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Abstract
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In the paper
“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.”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Results > CTCF and transcriptional regulation
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In the paper
“We detected a minor but reproducible reduction (∼10%) in the strength of compartmentalization upon CTCF depletion (Figure S4B).”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Results > Disruption of Local Insulation Does Not Affect Higher-Order Chromosome Folding
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In the paper
“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.”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Results > CTCF and transcriptional regulation
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In the paper
“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).”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Results > CTCF and transcriptional regulation
Strength:boosted· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“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).”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Results > CTCF Depletion Triggers Dramatic Loss of TAD Insulation
What the sources say
- Not checked yetcites Ji et al., 2016
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In the paper
“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.”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Results > CTCF Depletion Triggers Dramatic Loss of TAD Insulation
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In the paper
“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.”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Results > Auxin Treatment Severely Depletes CTCF from Chromatin
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In the paper
“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.”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Results > Disruption of Local Insulation Does Not Affect Higher-Order Chromosome Folding
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“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).”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Results > Acute CTCF Depletion with the Auxin-Inducible Degron System
What the sources say
- Not checked yetcites Morawska and Ulrich, 2013
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- It may state two separate claims as one. 24
- Probably not a substantial claim. 23
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Results > CTCF Depletion Triggers Dramatic Loss of TAD Insulation
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In the paper
“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).”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Results > CTCF and transcriptional regulation
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In the paper
“Washing off auxin led to reformation of insulated TADs in mESCs and NPCs but not resting astrocytes.”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Results > Loss of CTCF also Triggers Misfolding in Non-Cycling Cells
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In the paper
“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).”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Results > CTCF and transcriptional regulation
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In the paper
“with around half of the dysregulated being down-regulated and half up-regulated at each time-point.”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Results > CTCF and transcriptional regulation
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In the paper
“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).”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Results > Acute CTCF Depletion with the Auxin-Inducible Degron System
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Also stated in: § Acute CTCF Depletion with the Auxin-Inducible Degron System · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § CTCF is required for accumulating chromatin loops at CTCF sites · plain
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In the paper
“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).”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Results > Acute CTCF Depletion with the Auxin-Inducible Degron System
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In the paper
“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).”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Results > Loss of CTCF also Triggers Misfolding in Non-Cycling Cells
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In the paper
“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).”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Results > Acute CTCF Depletion with the Auxin-Inducible Degron System
What the sources say
- Not checked yetcites Sleutels et al., 2012 source
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Loss of CTCF led to loss of insulation at most boundaries (>80%, Figure 3B).”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Results > CTCF Depletion Triggers Dramatic Loss of TAD Insulation
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In the paper
“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).”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Results > CTCF and transcriptional regulation
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In the paper
“On a more global scale, we observed a slight but significant decrease in overall H3K27me3 levels (Figure S7B).”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Results > CTCF Binding Is Not a Direct Impediment to H3K27me3 Spreading in mESCs
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In the paper
“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).”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Results > Acute CTCF Depletion with the Auxin-Inducible Degron System
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In the paper
“Basal CTCF-AID-eGFP levels were slightly lower (1.5-2 fold) than when Tir1 was inserted at Rosa26 or randomly (Figure S3C)”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Method Details > Gene targeting
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In the paper
“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).”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Method Details > Plasmid Construction
What the sources say
- Not checked yetcites Nishimura et al., 2009 source
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In the paper
“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.”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Experimental Model and Subject Details > Neural progenitor cells and astrocytes
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- Also stated in: § Gene targeting · plain
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In the paper
“We noticed that only a handful of resistant clones were recovered, suggesting sub-optimal targeting – either because of the sgRNA or the targeting construct.”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Method Details > Gene targeting
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In the paper
“We noticed that Tir1 targeting with the Tigre targeting vector was at least 5-fold more efficient than with our Rosa26 targeting vector.”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Method Details > Gene targeting
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In the paper
“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.”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Method Details > Chromosome Conformation Capture Carbon-Copy (5C)
What the sources say
- Not checked yetcites Nora et al. 2012 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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In the paper
“We noticed the dual nickase underperformed for Rosa26 and recommend using a single nuclease strategy approach with the first sgRNA only.”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Method Details > Plasmid Construction
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In the paper
“The emerging model is that Cohesin packages the chromatin fiber while CTCF defines focal boundaries by constrains this packaging activity.”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Discussion > TAD Insulation and Transcriptional Regulation
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In the paper
“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).”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Results > Disruption of Local Insulation Does Not Affect Higher-Order Chromosome Folding
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In the paper
“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.”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Discussion > Local Insulation and A/B Compartmentalization Are Molecularly Separable Principles of Mammalian Genome Folding
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In the paper
“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).”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Discussion > TAD Insulation and Transcriptional Regulation
What the sources say
- Not checked yetcites Schwarzer et al., 2016
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In the paper
“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).”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Results > CTCF Binding Is Not a Direct Impediment to H3K27me3 Spreading in mESCs
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In the paper
“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.”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Method Details > Hi-C
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In the paper
“this analysis suggested the optimal threshold of 0.3, where the specificity of loop anchor recall dropped 3-fold.”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Quantification and Statistical Analysis > Hi-C analysis
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In the paper
“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.”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Method Details > Hi-C
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In the paper
“Over 95% of cells had one knock-in allele, of which 20% were homozygous.”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Method Details > Gene targeting
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In the paper
“Rosa26 PCR genotyping revealed this clone had undergone random insertion of the Tir1 cassette.”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Method Details > Gene targeting
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In the paper
“The clone analyzed here was homozygous for the integration and the puro cassette was still present in the final cell line.”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Method Details > Plasmid Construction
Strength:plain· not yet calibratedSingle caseTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Dissociation, wahs and Flow buffers were supplemented with auxin, when appropriate, to avoid re-expression of the CTCF-AID-eGFP fusion.”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Method Details > Flow Cytometry
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Negative controls (no ligase, no template, no 5C oligonucleotide) were included during each experiments to ensure the absence of contamination.”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Method Details > Chromosome Conformation Capture Carbon-Copy (5C)
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“For peak calling we followed the guidelines described in (Thomas et al., 2016).”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Quantification and Statistical Analysis > ChIP-seq Analysis
What the sources say
- Not checked yetcites Thomas et al., 2016 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The CTCF-AID NPC subclones did not survive freeze and thawing.”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Experimental Model and Subject Details > Neural progenitor cells and astrocytes
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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)).”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Method Details > Plasmid Construction
What the sources say
- Not checked yetcites Morawska and Ulrich, 2013
- Not checked yetcites Kubota et al., 2013 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Half of the clones were found to have undergone FlpO-mediated recombination. When homozygous both alleles always underwent recombination.”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Method Details > Gene targeting
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The consensus peak list was obtained by retaining peaks that overlapped for at least 1bp between biological replicates.”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Quantification and Statistical Analysis > ChIP-seq Analysis
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“FPKM provided in Supplementary Table 3 are means from 3 independent biological replicates.”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Quantification and Statistical Analysis > RNA-seq Analysis
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We selected the clone with the fewest GFP-positive cells (<1%) after 24h of auxin treatment.”
§ Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization > Method Details > Gene targeting
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measured
The cited source says what the claim attributes to it.
In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“(∼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
MinorThe step is described as RecJf exonuclease digestion and uses RecJf buffer, but the enzyme specified for that step is lambda exonuclease.
“RecJf exonuclease digestion was performed by resuspending the beads in 100μL 1× RecJf exonuclease buffer”
“supplemented with 30U lambda exonuclease (NEB) and incubating at 37°C for 30min.”
CTCF tag placement differs between Results and Methods
MinorThe 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.
“we targeted the stop codon of both Ctcf alleles to introduce a 44–amino acid version of the AID tag”
“To knock in the AID-eGFP cassette at the N-terinus of CTCF E14Tg2a passage 19 were transfected by microporation”
Different Tir1 targeting vectors specified for cell line #1
MinorThe 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.
“The Tir1 expression vector (pEN113) for the cell line analyzed by Hi-C (#1) was assembled”
“To knock in the Tir1-expressing cassette one homozygous CTCF-AID-eGFP clone was transfected as described above using a 100μL tip format and pEN114 as the targeting construct.”
Citations
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Items 801–900 of 1,001
Mahmood, S. R., Said, N. H. E., Gunsalus, K. C., & Percipalle, P. (2023) · Genome biology · doi:10.1186/s13059-023-02853-9 · Cited by 16
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Three-dimensional nuclear organisation and the DNA replication timing program
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Accessible gene borders establish a core structural unit for chromatin architecture in Arabidopsis
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“Compartmental domains exhibit both intra-domain and inter-domain interactions that are independent of CTCF and cohesin ( 11 , 14 ).”
BackgroundMolecular basis for SOX2-dependent regulation of super-enhancer activity
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“In flies where Fub function is abolished by the ablation of the critical effector protein, the two neighboring TADs fuse ( 81 ), and the homeotic gene located in one of the TADs becomes activated in the wrong part of the fly embryo by the enhancer located in the other TAD ( 64 , 70 , 79 ).”
BackgroundSun, D., Zhu, Y., Peng, W., Zheng, S., Weng, J., Dong, S., Li, J., Chen, Q., Ge, C., Liao, L., et al. (2024) · Genome biology · doi:10.1186/s13059-024-03327-2 · Cited by 15
“Although CTCF has been recognized as an insulator in the formation of TAD boundaries [37, 38], our data did not reveal any significant changes in the number and width of TADs, the insulation score of TAD boundaries, or the interaction frequency between neighboring TADs (Fig.”
BackgroundCell-type-specific loops linked to RNA polymerase II elongation in human neural differentiation
Titus, K. R., Simándi, Z., Chandrashekar, H., Paquet, D., & Phillips‐Cremins, J. E. (2024) · Cell Genomics · doi:10.1016/j.xgen.2024.100606 · Cited by 17
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Evolution of 3D Chromatin Folding
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A combination of transcription factors mediates inducible interchromosomal contacts
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BackgroundMethodResultInfluentialInterplay between regulatory elements and chromatin topology in cellular lineage determination
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“TAD structure, but left active and inactive genome compartments properly segregated (47).”
BackgroundEnhancer Function in the 3D Genome
Razin, S. V., Ulianov, S. V., & Iarovaia, O. V. (2023) · Genes · doi:10.3390/genes14061277 · Cited by 15
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Large domains of heterochromatin direct the formation of short mitotic chromosome loops
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“First, because CTCF plays a key role in the formation of TADs in interphase in part through the regulation of the loop-extruding activity of cohesin (Dixon et al., 2012; Nora et al., 2017; Sanborn et al., 2015), we performed a search for CTCF consensus binding sites across the Sp-DNA insert and neighbouring mouse DNA…”
MethodSelf-citationMagnitov, M. D., Garaev, A. K., Tyakht, A., Ulianov, S. V., & Razin, S. V. (2022) · BMC Bioinformatics · doi:10.1186/s12859-022-04654-6 · Cited by 17
“As revealed by the depletion of subunits of the cohesin complex [11] and CTCF [12], the overwhelming majority of TADs and loops in mammalian cells are established by cohesin-driven CTCF-restricted chromatin fiber extrusion.”
BackgroundJaber, M., Radwan, A., Loyfer, N., Abdeen, M., Sebban, S., Khatib, A., Yassen, H., Kolb, T., Zapatka, M., Makedonski, K., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-31131-8 · Cited by 15
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Disruption of regulatory domains and novel transcripts as disease‐causing mechanisms
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“[8,54,57] Third, using mouse embryonic stem cells (mESCs), a recent study found that enhancer-promoter interactions and transcription are largely insensitive to acute depletion of CTCF, cohesin, WAPL, or YY1 (Ying Yang 1).”
BackgroundZhang, G., Li, Y., & Wei, G. (2023) · Communications Biology · doi:10.1038/s42003-023-05141-1 · Cited by 16
“The extreme case of the change of TAD insulation has been reported by Nora, E. P. et al. 56 , in which the acute depletion of CTCF leads to dramatic loss of TAD insulation but only has modest impacts on gene transcription.”
Topology regulatory elements: From shaping genome architecture to gene regulation
Chen, L., & Long, H. K. (2023) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2023.102723 · Cited by 15
“Indeed, the majority of genes are able to recruit enhancers and initiate transcription normally in the face of acute degradation of CTCF [21,38–41].”
BackgroundTet-mediated DNA methylation dynamics affect chromosome organization
Tian, H., Luan, P., Liu, Y., & Li, G. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae054 · Cited by 15
“…of TADs and chromatin looping were disrupted, revealing that the formations of TADs and compartments result from distinct mechanisms: cohesin-independent compartment segregation defined by chromatin states and cohesin-dependent loop extrusion for TAD boundaries and chromatin loops ( 61 ,62 ).”
BackgroundGender-specific genetic and epigenetic signatures in cardiovascular disease
Bridges, J., Ramirez-Guerrero, J. A., & Rosa‐Garrido, M. (2024) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2024.1355980 · Cited by 15
The PTM profiling of CTCF reveals the regulation of 3D chromatin structure by O-GlcNAcylation
Tang, X., Zeng, P., Liu, K., Li, Q., Sun, Y., Liu, X., Lu, L., Wei, C., Wang, J., Jiang, S., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-47048-3 · Cited by 17
“To examine the function of the CTCF O-GlcNAcylation, we used CTCF-mAID mESCs as donor cells 14 , and transduced the cells with vector encoding WT_CTCF or T668A O-GlcNAc-de fi cient CTCF (MUT_CTCF), respectively (Fig.”
Jain, R., & Epstein, J. A. (2024) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-44087-8_18 · Cited by 16
Zhang, J., Hu, G., Lu, Y., Ren, H., Huang, Y., Wen, Y., Ji, B., Wang, D., Wang, H., Liu, H., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-49684-1 · Cited by 18
“Alterations in the expression level or insuf fi - cient dosage of CTCF atthe cellularlevel can result in shifts in cell fate, potentiallyleadingtocellulardemise 7,10 – 12 .”
InfluentialMulet‐Lazaro, R., van Herk, S., Nuetzel, M., Sijs‐Szabó, A., Díaz, N., Kelly, K., Erpelinck-Verschueren, C. A. J., Schwarzfischer, L., Stanewsky, H., Ackermann, U., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-49811-y · Cited by 17
Dynamics of transcriptional enhancers and chromosome topology in gene regulation
Yokoshi, M., & Fukaya, T. (2019) · Development Growth & Differentiation · doi:10.1111/dgd.12597 · Cited by 14
“…depletion of CTCF or Rad21, a kleisin subunit of the cohesin complex, eliminates essentially all TADs observed with population- based Hi- C methods (Nora et al., 2017; Rao et al., 2017; Wutz et al., 2017), highlighting the functional importance of these proteins in TAD formation and maintenance.”
BackgroundMethodUnraveling the multiplex folding of nucleosome chains in higher order chromatin
Grigoryev, S. A., & Schubert, M. (2019) · Essays in Biochemistry · doi:10.1042/ebc20180066 · Cited by 15
Bernardi, G. (2019) · BioEssays · doi:10.1002/bies.201900106 · Cited by 17
Recent advances in the spatial organization of the mammalian genome
Kumar, Y., Sengupta, D., & Bickmore, W. A. (2020) · Journal of Biosciences · doi:10.1007/s12038-019-9968-1 · Cited by 15
“Loop extrusion supports observed TAD structures in Hi-C data and accurately predicts the formation of new boundaries upon deletion of CTCF binding sites (Fudenberg et al. 2016; Sanborn et al. 2015; Nora et al. 2017).”
BackgroundA unified framework for inferring the multi-scale organization of chromatin domains from Hi-C
Bak, J. H., Kim, M. H., Liu, L., & Hyeon, C. (2021) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1008834 · Cited by 13
“We therefore identify these CDs as the “meta-TADs”, a higher-order structure of TADs, adopting the term of Ref.”
Deep Learning of Sequence Patterns for CCCTC-Binding Factor-Mediated Chromatin Loop Formation
Kuang, S., & Wang, L. (2020) · Journal of Computational Biology · doi:10.1089/cmb.2020.0225 · Cited by 15
“Moreover, depletion of CTCF or cohesin results in the loss of loop structures (Nora et al., 2017; Rao et al., 2017).”
Induction of a chromatin boundary in vivo upon insertion of a TAD border
Willemin, A., Lopez‐Delisle, L., Bolt, C. C., Gadolini, M.-L., Duboule, D., & Rodríguez-Carballo, E. (2021) · PLoS Genetics · doi:10.1371/journal.pgen.1009691 · Cited by 14
Visualizing Live Chromatin Dynamics through CRISPR-Based Imaging Techniques
Chaudhary, N., Im, J., Nho, S.-H., & Kim, H. (2021) · Molecules and Cells · doi:10.14348/molcells.2021.2254 · Cited by 16
“TAD boundaries are highly enriched with the insulator protein CCCTC-binding factor (CTCF) and the cohesin complex, which are strongly colocalized (Nora et al., 2017; Rao et al., 2017; Zuin et al., 2014).”
BackgroundMultiple parameters shape the 3D chromatin structure of single nuclei at the doc locus in Drosophila
Götz, M., Messina, O., Espínola, S., Fiche, J.-B., & Nöllmann, M. (2022) · Nature Communications · doi:10.1038/s41467-022-32973-y · Cited by 16
“Population-average TADs require the presence of CTCF and cohesin in mammals 38,56–58 , and can first be detected at the zygotic genome activation step in multiple species 23,24,59–61 .”
Integrating transposable elements in the 3D genome
Bousios, A., Nützmann, H., Buck, D., & Michieletto, D. (2020) · Mobile DNA · doi:10.1186/s13100-020-0202-3 · Cited by 16
Controlling gene activation by enhancers through a drug-inducible topological insulator
Tsujimura, T., Takase, O., Yoshikawa, M., Sano, E., Hayashi, M., Hoshi, K., Takato, T., Toyoda, A., Okano, H., & Hishikawa, K. (2020) · eLife · doi:10.7554/elife.47980 · Cited by 16
“Loss of cohesin or CTCF resulted in disappearance of contact domains (Gassler et al., 2017; Nora et al., 2017; Rao et al., 2017; Schwarzer et al., 2017; Wutz et al., 2017).”
BackgroundConstructing Auxin-Inducible Degron Mutants Using an All-in-One Vector
Yesbolatova, A., Saito, Y., & Kanemaki, M. T. (2020) · Pharmaceuticals · doi:10.3390/ph13050103 · Cited by 13
Are the processes of DNA replication and DNA repair reading a common structural chromatin unit?
Mamberti, S., & Cardoso, M. C. (2020) · Nucleus · doi:10.1080/19491034.2020.1744415 · Cited by 12
“[48] Nora EP, Goloborodko A, Valton AL, et al.”
BackgroundInfluentialGenomic context sensitivity of insulator functionPreprint
Ribeiro-dos-Santos, A. M., Hogan, M. S., Luther, R. D., Brosh, R., & Maurano, M. T. (2022) · Genome Research · doi:10.1101/gr.276449.121 · Cited by 14
“A strict barrier definition of insulator function is difficult to reconcile with these results, or with studies showing perturbations of CTCF binding yield readily detectable alterations in genome organization but not of gene expression (Nora et al. 2017; Zhang et al. 2020).”
ResultSex-determining 3D regulatory hubs revealed by genome spatial auto-correlation analysisPreprint
Mota-Gómez, I., Rodríguez, J. A., Dupont, S. M., Lao, O., Jedamzick, J., Kuhn, R., Lacadie, S., Garcia-Moreno, S. A., Hurtado, A., Acemel, R. D., et al. (2022) · bioRxiv · doi:10.1101/2022.11.18.516861 · Cited by 9
Mutations of PDS5 genes enhance TAD-like domain formation in Arabidopsis thaliana
Göbel, A.-M., Zhou, S., Wang, Z., Tzourtzou, S., Himmelbach, A., Zheng, S., Pradillo, M., Liu, C., & Jiang, H. L. (2024) · Nature Communications · doi:10.1038/s41467-024-53760-x · Cited by 17
“10).”
Bryan, A. F., Justice, M., Stutzman, A. V., McKay, D. J., & Dowen, J. M. (2025) · Epigenetics & Chromatin · doi:10.1186/s13072-025-00598-2 · Cited by 14
Establishment of chromatin architecture interplays with embryo hypertranscription
Yu, G., Xu, K., Xia, W., Zhang, K., Xu, Q., Li, L., Lin, Z., Liu, L., Liu, B., Du, Z., et al. (2025) · Nature · doi:10.1038/s41586-025-09400-5 · Cited by 16
RNA-binding proteins mediate the maturation of chromatin topology during differentiation
Dehingia, B., Milewska, M., Janowski, M., Rafiee, M., Abbas, M., Piotrowska, A., Senge, J. F., Blaut, P., Walsh, D., Severino, J., et al. (2025) · Nature Cell Biology · doi:10.1038/s41556-025-01735-5 · Cited by 17
Organization of replicated chromosomes by DNA loops and sister chromatid cohesion
Ochs, F., & Gerlich, D. W. (2026) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-025-00933-1 · Cited by 16
Beagrie, R. A., & Pombo, A. (2017) · Nature · doi:10.1038/547034a · Cited by 13
Boyling, A., Pérez‐Siles, G., & Kennerson, M. L. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.842860 · Cited by 15
Genetic and Epigenetic Interplay Define Disease Onset and Severity in Repeat Diseases
Barbé, L., & Finkbeiner, S. M. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.750629 · Cited by 15
Wang, R., Xu, Q., Wang, C., Tian, K., Wang, H., & Ji, X. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad401 · Cited by 13
Pugacheva, E. M., Bhatt, D. N., Rivero-Hinojosa, S., Tajmul, M., Fedida, L. M., Price, E., Ji, Y. J., Loukinov, D. I., Strunnikov, A. V., Ren, B., et al. (2024) · Genome biology · doi:10.1186/s13059-024-03175-0 · Cited by 16
Mechanistic drivers of chromatin organization into compartments
Harris, H. L., & Rowley, M. J. (2024) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2024.102193 · Cited by 13
cBAF generates subnucleosomes that expand OCT4 binding and function beyond DNA motifs at enhancers
Nocente, M. C., Karamitsos, A. M., Drouineau, E., Soleil, M., Albawardi, W., Dulary, C., Ribiérre, F., Picaud, H., Alibert, O., Acker, J., et al. (2024) · Nature Structural & Molecular Biology · doi:10.1038/s41594-024-01344-0 · Cited by 18
Tajmul, M., Bhatt, D. N., Ruje, L., Price, E., Ji, Y. J., Loukinov, D. I., Teif, V. B., Lobanenkov, V. V., & Pugacheva, E. M. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf587 · Cited by 14
The formation of chromatin domains involves a primary step based on the 3-D structure of DNA
Bernardi, G. (2018) · Scientific Reports · doi:10.1038/s41598-018-35851-0 · Cited by 14
Su, G., Wang, W., Chen, J., Liu, M., Zheng, J., Guo, D., Bi, J., Zhao, Z., Shi, J., Zhang, L., et al. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100413 · Cited by 14
“(17) found that CTCF loss promoted disappearance of TADs, revealing CTCT as essential for maintaining TAD formation.”
BackgroundWatson, A. T., Hassell‐Hart, S., Spencer, J., & Carr, A. M. (2021) · Genes · doi:10.3390/genes12060882 · Cited by 14
A Cohesin Traffic Pattern Genetically Linked to Gene Regulation
Valton, A.-L., Dekker, J., Venev, S. V., Mair, B., Khokhar, E. S., Pai, A. A., & Moffat, J. (2021) · HAL · Cited by 18
Self-citationRIF1 Links Replication Timing with Fork Reactivation and DNA Double-Strand Break Repair
Błasiak, J., Szczepańska, J., Sobczuk, A., Fila, M., & Pawłowska, E. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222111440 · Cited by 16
MoDLE: high-performance stochastic modeling of DNA loop extrusion interactions
Rossini, R., Kumar, V., Mathelier, A., Rognes, T., & Paulsen, J. (2022) · bioRxiv · doi:10.1186/s13059-022-02815-7 · Cited by 14
“Similarly, depletion of CTCF induces loss of loops and TADs [24, 27].”
BackgroundPing, W., Sheng, Y., Hu, G., Zhong, H., Li, Y., Liu, Y., Luo, W., Yan, C., Wen, Y., Wang, X., et al. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad219 · Cited by 13
Greenberg, M., Teissandier, A., Walter, M., Noordermeer, D., & Bourc’his, D. (2019) · eLife · doi:10.7554/elife.44057 · Cited by 15
“Mammalian genomes are physically subdivided into ‘regulatory neighbor- hoods’ known as topologically associated domains (TADs), which average roughly one megabase in size (Dixon et al., 2012; Nora et al., 2012); available Hi-C data from mouse ESCs indicates that the Zdbf2 locus exists within an ‘inter-TAD’ that spans…”
BackgroundMethodInfluentialKim, Y. W., Kang, Y., Kang, J., & Kim, A. (2020) · The FASEB Journal · doi:10.1096/fj.202001526r · Cited by 14
The Bromodomain Containing 8 (BRD8) transcriptional network in human lung epithelial cells
Browne, J. A., NandyMazumdar, M., Paranjapye, A., Leir, S., & Harris, A. (2021) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2021.111169 · Cited by 14
“CTCF has a major role as an architectural protein involved in chromatin organization (Bonev and Cavalli, 2016; Ghirlando and Felsenfeld, 2016; Ong and Corces, 2014), though it may also modulate gene expression directly, by binding to transcription start sites (Nora et al., 2017).”
BackgroundPrinciples of Meiotic Chromosome AssemblyPreprint
Schalbetter, S., Fudenberg, G., Baxter, J., Pollard, K., & Neale, M. (2018) · bioRxiv · doi:10.1101/442038 · Cited by 16
Kubo, N., Ishii, H., Xiong, X., Bianco, S., Meitinger, F., Hu, R., Hocker, J. D., Conte, M., Gorkin, D. U., Yu, M., et al. (2020) · bioRxiv · doi:10.1101/2020.03.21.001693 · Cited by 10
Live-cell 3D single-molecule tracking reveals how NuRD modulates enhancer dynamicsPreprint
Basu, S., Shukron, O., Hall, D., Parutto, P., Ponjavic, A., Shah, D., Boucher, W., Lando, D., Zhang, W., Reynolds, N., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.04.03.003178 · Cited by 14
RNA polymerase II is required for spatial chromatin reorganization following exit from mitosisPreprint
Zhang, S., Übelmesser, N., Josipovic, N., Forte, G., Slotman, J., Chiang, M., Gothe, H., Gusmao, E., Becker, C., Altmuller, J., et al. (2020) · bioRxiv · doi:10.1101/2020.10.27.356915 · Cited by 105
“Given that loop formation relies on the loading and DNA extrusion by cohesin complexes ending up at CTCF-marked anchors ( 10 – 13 , 16 ), we examined how the levels of CTCF/cohesin subunits change in reentry cells following auxin treatment.”
InfluentialA cohesin traffic pattern genetically linked to gene regulationPreprint
Valton, A.-L., Venev, S. V., Mair, B., Khokhar, E. S., Tong, A. H. Y., Ušaj, M., Chan, K. S. K., Pai, A. A., Moffat, J., & Dekker, J. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.07.29.454218 · Cited by 15
“All these features disappear when CTCF or cohesin is depleted (Nora et al., 2017; Rao et al., 2017; Wutz et al., 2017) or CTCF-sites are deleted (Hnisz et al., 2016; Narendra et al., 2015; Sanborn et al., 2015; Splinter et al., 2006; de Wit et al., 2015), while CTCF-CTCF loops are enhanced when the…”
BackgroundResultInfluentialSelf-citationSMC motor proteins extrude DNA asymmetrically and contain a direction switchPreprint
Barth, R., Davidson, I., van der Torre, J., Taschner, M., Gruber, S., Peters, J.-M., & Dekker, C. (2023) · bioRxiv · doi:10.1101/2023.12.21.572892 · Cited by 14
Beckwith, K. S., Ødegård-Fougner, Ø., Morero, N. R., Barton, C., Schueder, F., Tang, W., Alexander, S., Peters, J. M., Jungmann, R., Birney, E., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-61689-y · Cited by 13
“3f), consistent with CTCFs role as a boundary factor for loop formation 5,41 .”
Precise control of chromatin loop extrusion enhances sustainable green revolution yield in rice
Liu, Q., Liu, H., Sun, L., Wang, D., Sun, X., Wu, K., Ye, Y., Wang, Y., Wang, S., Zhong, N., et al. (2025) · Nature Genetics · doi:10.1038/s41588-025-02376-y · Cited by 13
“…and mediate H3K27me3 spreading 31,32 , ChIP–PCR assays demonstrated that loop anchors were associated with allele-specific methylation at lysine 27 of histone H3 and suppression of RCN2 , but mutations of CCCTC insulator elements abolished chromatin loop formation and led to decreased H3K27me3…”
Polymer models are a versatile tool to study chromatin 3D organization
Esposito, A., Bianco, S., Fiorillo, L., Conte, M., Abraham, A., Musella, F., Nicodemi, M., Prisco, A., & Chiariello, A. M. (2021) · Biochemical Society Transactions · doi:10.1042/bst20201004 · Cited by 14
Cis-Regulatory Control of Mammalian Sex Determination
Ridnik, M., Schoenfelder, S., & Gonen, N. (2021) · Sexual Development · doi:10.1159/000519244 · Cited by 14
“It is important to note that the mild gene expression changes upon cohesin or CTCF removal were mainly observed in vitro under controlled cell culture conditions [Haarhuis et al., 2017; Nora et al., 2017; Rao et al., 2017; Thiecke et al., 2020].”
BackgroundYe, Y., Zhang, S., Gao, L., Zhu, Y., & Zhang, J. (2023) · Advanced Science · doi:10.1002/advs.202205162 · Cited by 12
Transcription factor expression is the main determinant of variability in gene co‐activity
van Duin, L., Krautz, R., Rennie, S., & Andersson, R. (2023) · Molecular Systems Biology · doi:10.15252/msb.202211392 · Cited by 11
“Assessment of the downstream effects of perturbations of these networks helps to identify important regulatory processes and pathways implicated in disease.”
BackgroundRizvi, S., Chhabra, A., Tripathi, A., & Tyagi, R. K. (2023) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2023.112069 · Cited by 13
Palmisano, I., Liu, T., Gao, W., Zhou, L., Merkenschlager, M., Müller, F., Chadwick, J., Toscano-Rivalta, R., Kong, G., King, J. W. D., et al. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2402518121 · Cited by 13
“Such 3D organization arises from the coordinated activity of cohesin and CCCTC - binding factor (CTCF) ( 7 – 10 ).”
Genome folding and zygotic genome activation in mammalian preimplantation embryos
Bondarieva, A., & Tachibana, K.-E. K. (2024) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2024.102268 · Cited by 15
High-resolution CTCF footprinting reveals impact of chromatin state on cohesin extrusion
Sept, C., Tak, Y. E., Goel, V. Y., Bhakta, M. S., Cerda-Smith, C. G., Hutchinson, H. M., Blanchette, M., Eyler, C. E., Johnstone, S. E., Joung, J. K., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-57775-w · Cited by 17
Kim, M., Wang, P., Clow, P. A., Chien, E., Wang, X., Peng, J., Chai, H., Liu, X., Lee, B., Ngan, C. Y., et al. (2026) · Nature Structural & Molecular Biology · doi:10.1038/s41594-025-01708-0 · Cited by 13
“…conundrum in chromatin biology; namely, that acute depletion of chromatin architectural proteins has only a marginal effect on gene expression despite the loss of chromatin loops genome-wide 18,19 ; transcription of most genes is maintained by short-range loops that are cohesin independent (Fig.”
InfluentialA (3D-Nuclear) Space Odyssey: Making Sense of Hi-C Maps
Mota-Gómez, I., & Lupiáñez, D. G. (2019) · Genes · doi:10.3390/genes10060415 · Cited by 16
Spatial genome exploration in the context of cognitive and neurological disease
Rajarajan, P., Borrman, T. M., Liao, W., Espeso‐Gil, S., Chandrasekaran, S., Jiang, Y., Weng, Z., Brennand, K., & Akbarian, S. (2019) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2019.05.007 · Cited by 13
“Because the majority of functional elements in human non-coding DNA, including enhancers and repressors, are not bound to the nearest TSS but instead tethered via chromosomal contacts to genes located elsewhere on the chromosome[50], it is unsurprising therefore that, as discussed in[26], non-3DG based approaches such…”
BackgroundTechnologies to study spatial genome organization: beyond 3C
Übelmesser, N., & Papantonis, A. (2019) · Briefings in Functional Genomics · doi:10.1093/bfgp/elz019 · Cited by 13
A Newly Assigned Role of CTCF in Cellular Response to Broken DNAs
Kang, M. A., & Lee, J.-S. (2021) · Biomolecules · doi:10.3390/biom11030363 · Cited by 14
“This model is supported by degradation or depletion of RAD21 and CTCF loss [30,53,54].”
MethodScourzic, L., Salataj, E., & Apostolou, E. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.669881 · Cited by 16
The two waves in single-cell 3D genomics
Ulianov, S. V., & Razin, S. V. (2021) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2021.05.021 · Cited by 15
The Mutational Landscape of Myeloid Leukaemia in Down Syndrome
de Castro, C. P. M., Cadefau-Fabregat, M., & Cuartero, S. (2021) · Cancers · doi:10.3390/cancers13164144 · Cited by 16
Metadata
- 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
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-05
- Volume
- 169
- Issue
- 5
- Pages
- 930-944.e22
- ISSN
- 0092-8674 (ISSN-L)
- 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
- FWCI
- 67.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- 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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