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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 501–600 of 1,001
The genetic architecture of DNA replication timing in human pluripotent stem cells
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Chromosome compartmentalization alterations in prostate cancer cell lines model disease progression
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“2014), and CTCF occupancy at nearby sites contributes to the maintenance of gene expression and stable chromatin structure (Nora et al. 2017; Rao et al. 2017; Schwarzer et al. 2017; Bintu et al. 2018).”
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“Moreover, depleting the complexes responsible for TAD boundary formation completely abolishes TAD structures, yet only mildly affects gene expression ( 25–28 ).”
BackgroundEpigenetic regulatory layers in the 3D nucleus
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DNA sequence-dependent chromatin architecture and nuclear hubs formation
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Computational approaches from polymer physics to investigate chromatin folding
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The Role of Bromodomain and Extraterminal Motif (BET) Proteins in Chromatin StructurePreprint
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“Prolonged or acute depletion of CTCF leads to increased cross-TAD boundary contacts and varying degrees of reduction in TAD boundary insulation (Zuin et al. 2014; Kubo et al. 2017; Nora et al. 2017).”
BackgroundActive enhancers strengthen insulation by RNA-mediated CTCF binding at chromatin domain boundariesPreprint
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“2020) and are dependent on CTCF and cohesin (Nora et al. 2017; Rao et al. 2017; Schwarzer et al. 2017; Wutz et al. 2017; Szabo et al. 2020).”
BackgroundInfluentialThe global and promoter-centric 3D genome organization temporally resolved during a circadian cycle
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“Several studies have shown that the ablation of CTCF or cohesin has limited effects on gene expression and histone modifications, although it causes TAD loss, suggesting that transcriptional regulation might be preserved even if TADs are almost completely disrupted (Nora et al., 2017; Schwarzer et al., 2017).”
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“However, loss of H3K27ac at enhancer regions did not affect the chromatin accessibility, transcription and self-renewal of mouse embryonic stem cells (mESCs) (34).”
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Condensin DC loads and spreads from recruitment sites to create loop-anchored TADs in C. elegans
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Rec8 Cohesin: A Structural Platform for Shaping the Meiotic Chromosomes
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SMARCB1 loss activates patient-specific distal oncogenic enhancers in malignant rhabdoid tumors
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“This is in line with previous literature showing that at least 85% of CTCF depletion is needed to induce major changes in 3D genome organization 55 .”
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“With evidence that CTCF binding anchors genomic looping, [49] these observations motivated chromatin structural studies.”
BackgroundRoles of CTCF in conformation and functions of chromosome
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“Interestingly, the clearest trends are seen not only for several TFs but also for the CTFC, Smc1a, and Smc3 proteins, which have biological roles involving the spatial association of chromatin, e.g., via loop formation [26, 45, 46].”
BackgroundRapid depletion of CTCF and cohesin proteins reveals dynamic features of chromosome architecturePreprint
Liu, N.-Q., Magnitov, M. D., Schijns, M. M. G. A., van Schaik, T., van der Weide, R. H., Teunissen, H., van Steensel, B., & de Wit, E. (2021) · bioRxiv · doi:10.1101/2021.08.27.457977 · Cited by 34
“The APA and ATA analyses showed that these architectural features are lost in a genome-wide fashion (Figure S3B), in correspondence with observations in CTCF depletion experiments (Nora et al., 2017; Wutz et al., 2017).”
BackgroundResultChromosome compartmentalization: causes, changes, consequences, and conundrums
Li, H., Playter, C., Das, P., & McCord, R. P. (2024) · Trends in Cell Biology · doi:10.1016/j.tcb.2024.01.009 · Cited by 36
Applebaum, M. A., Barr, E. K., Karpus, J., West-Szymanski, D. C., Oliva, M., Sokol, E., Zhang, S., Zhang, Z., Zhang, W., Chlenski, A., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-2829 · Cited by 35
“CTCF/ cohesin has been shown to regulate topologically associated domains (TAD) for organizing larger scale chromatin structures (47) and have a direct interaction with both trimethylation of histone 3 at lysine 27 (H3K27me3), 5-mC, and 5-hmC (48, 49).”
BackgroundMechanisms of maternal intergenerational epigenetic inheritance
Stäubli, A., & Peters, A. H. F. M. (2021) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2021.01.008 · Cited by 36
Meléndez-Ramírez, C., Durán, R. C., Barrios‐García, T., Giacoman-Lozano, M., López-Ornelas, A., Herrera-Gamboa, J. G., Estudillo, E., Soto‐Reyes, E., Velasco, I., & Treviño, V. (2021) · Scientific Reports · doi:10.1038/s41598-021-96263-1 · Cited by 38
Ligand-induced degrons for studying nuclear functions
Kanemaki, M. T. (2022) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2021.12.006 · Cited by 35
Bedi, Y. S., Wang, H., Thomas, K. N., Basel, A., Prunier, J., Robert, C., & Golding, M. C. (2022) · Scientific Reports · doi:10.1038/s41598-022-12188-3 · Cited by 35
Rheinberger, M., Costa, A. L., Kampmann, M., Glavaš, D., Shytaj, I. L., Sreeram, S., Penzo, C., Tibroni, N., García‐Mesa, Y., Leskov, K., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112110 · Cited by 33
Cohesin maintains replication timing to suppress DNA damage on cancer genes
Wu, J., Liu, Y., Zhangding, Z., Liu, X., Chen, A., Gan, T., Liang, H., Guo, Y., Chen, M., Liu, Y., et al. (2023) · Nature Genetics · doi:10.1038/s41588-023-01458-z · Cited by 33
Live-cell three-dimensional single-molecule tracking reveals modulation of enhancer dynamics by NuRD
Basu, S., Shukron, O., Hall, D., Parutto, P., Ponjavic, A., Shah, D., Boucher, W., Lando, D., Zhang, W., Reynolds, N., et al. (2023) · Nature Structural & Molecular Biology · doi:10.1038/s41594-023-01095-4 · Cited by 44
“We therefore carried out CUT&RUN experiments to study chromatin binding of CTCF and cohesin, which have a key role in loop and TAD formation 13,58–63 .”
MethodExtensive mutual influences of SMC complexes shape 3D genome folding
Zhao, H., Shu, L., Qin, S., Lyu, F., Liu, F., Lin, E., Xia, S., Wang, B., Wang, M., Shan, F., et al. (2025) · Nature · doi:10.1038/s41586-025-08638-3 · Cited by 33
Loguercio, S., Barajas-Mora, E. M., Shih, H., Krangel, M. S., & Feeney, A. J. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00425 · Cited by 32
The 3D Genome as a Target for Anticancer Therapy
Kantidze, O. L., Gurova, K. V., Studitsky, V. M., & Razin, S. V. (2019) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2019.09.011 · Cited by 36
Maksimenko, O. G., Фурсенко, Д. В., Belova, E., & Georgiev, P. G. (2021) · Acta Naturae · doi:10.32607/actanaturae.11206 · Cited by 32
Long-distance association of topological boundaries through nuclear condensates
Gamliel, A., Meluzzi, D., Oh, S., Jiang, N., Destici, E., Rosenfeld, M. G., & Nair, S. J. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2206216119 · Cited by 38
Mechanisms of Interaction between Enhancers and Promoters in Three Drosophila Model Systems
Kyrchanova, O., Sokolov, V., & Georgiev, P. G. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032855 · Cited by 32
The p-Arms of Human Acrocentric Chromosomes Play by a Different Set of Rules
McStay, B. (2023) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-101122-081642 · Cited by 36
Galupa, R., & Heard, É. (2017) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2017.82.035030 · Cited by 30
“A recent study using a degron system to deplete the CTCF protein, which abolished most TADs in ES cells, revealed that H3K27me3 domains remained largely unchanged in this context (Nora et al. 2017).”
BackgroundInfluentialCohesin-mediated 3D contacts tune enhancer-promoter regulationPreprint
Guckelberger, P., Doughty, B. R., Munson, G., Rao, S. S. P., Tan, Y., Cai, X. S., Fulco, C. P., Nasser, J., Mualim, K. S., Bergman, D. T., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.07.12.603288 · Cited by 33
“However, the depletion of these architectural proteins have minimal impacts on gene expression, despite the loss of loops and contact domains 23–26 .”
BackgroundResultMechanisms of enhancer-promoter communication and chromosomal architecture in mammals and Drosophila
Kyrchanova, O. V., Bylino, O. V., & Georgiev, P. G. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.1081088 · Cited by 29
“There are a number of experimental data that CP190, in cooperation with BEAF, Chromator and Z4, can participate in the organization of TADs (Ramírez et al., 2018;Wang et al., 2018; Pal et al., 2019).”
BackgroundInfluentialGene functioning and storage within a folded genome
Razin, S. V., & Ulianov, S. V. (2017) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-017-0050-4 · Cited by 37
Patel, P. J., Ren, Y., & Yan, Z. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106192 · Cited by 35
Histone H1.0 couples cellular mechanical behaviors to chromatin structure
Hu, S., Chapski, D. J., Gehred, N., Kimball, T. H., Gromova, T., Flores, A., Rowat, A. C., Chen, J., Packard, R. R. S., Olszewski, E., et al. (2024) · Nature Cardiovascular Research · doi:10.1038/s44161-024-00460-w · Cited by 32
“0, mirroring distinct effects shown for other chromatin structural proteins, such as CTCF in primordial versus terminally differentiated cells 63,64 .”
Genome organization at different scales: nature, formation and function
Serizay, J., & Ahringer, J. (2018) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2018.03.009 · Cited by 35
“A series of recent studies directly investigated the roles of cohesin and CTCF in interphase chromosome organization by removing them in mammalian cells [16,54].”
BackgroundInfluentialSpatial Genome Organization: From Development to Disease
Sivakumar, A., Heras, J. I. D. L., & Schirmer, E. C. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00018 · Cited by 34
“This relocation was accompanied by a change from regular to irregular territory shape (Orsztynowicz et al., 2017).”
BackgroundRosario, B. C. D., Kriz, A. J., Rosario, A. M. D., Anselmo, A. N., Fry, C. J., White, F. M., Sadreyev, R. I., & Lee, J. T. (2019) · eLife · doi:10.7554/elife.42341 · Cited by 30
“As previous studies had shown that CTCF binding is important for formation of TAD borders (Sanborn et al., 2015; Nora et al., 2017), we decided to examine the impact of overexpressing wild-type CTCF, S224A or S224E on nuclear architecture using HYbrid Capture Hi-C (Hi-C(2)), a costeffective alternative to genome-wide…”
BackgroundMethodSerebreni, L., & Stark, A. (2020) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2020.11.009 · Cited by 32
Tissue-specific Grb10/Ddc insulator drives allelic architecture for cardiac development
Juan, A. M., Foong, Y. H., Thorvaldsen, J. L., Lan, Y., Leu, N. A., Rurik, J. G., Li, L., Krapp, C. J., Rosier, C. L., Epstein, J. A., et al. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.08.021 · Cited by 28
Stable H3K4me3 is associated with transcription initiation during early embryo development
Huang, X., Gao, X., Li, W., Jiang, S., Li, R., Hong, H., Zhao, C., Zhou, P., Chen, H., Bo, X., et al. (2019) · Bioinformatics · doi:10.1093/bioinformatics/btz173 · Cited by 31
Role of lamins in 3D genome organization and global gene expression
Kim, Y., Zheng, X., & Zheng, Y. (2019) · Nucleus · doi:10.1080/19491034.2019.1578601 · Cited by 32
Systematic assessment of ISWI subunits shows that NURF creates local accessibility for CTCF
Iurlaro, M., Masoni, F., Flyamer, I. M., Wirbelauer, C., Iskar, M., Burger, L., Giorgetti, L., & Schübeler, D. (2024) · Nature Genetics · doi:10.1038/s41588-024-01767-x · Cited by 35
“14) or upon CTCF degradation 30 (Extended Data Fig.”
InfluentialCTCF depletion decouples enhancer-mediated gene activation from chromatin hub formation
Karpińska, M. A., Zhu, Y., Ghazvini, Z. F., Ramasamy, S., Barbieri, M., Cao, T. B. N., Varahram, N., Aljahani, A., Lidschreiber, M., Papantonis, A., et al. (2025) · Nature Structural & Molecular Biology · doi:10.1038/s41594-025-01555-z · Cited by 35
“Consistent with previous CTCF perturbation studies 47,61,66–70 , we do not observe widespread misregulation of gene expression in the absence of CTCF.”
Developmentally regulated higher-order chromatin interactions orchestrate B cell fate commitment
Boya, R., Yadavalli, A. D., Nikhat, S., Kurukuti, S., Palakodeti, D., & Pongubala, J. M. R. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx722 · Cited by 30
“Further it was demonstrated that loss of CTCF results in dose dependent insulation defects at most of the TAD boundaries (13).”
BackgroundChen, F., Yuan, H., Wu, W., Chen, S., Yang, Q., Wang, J., Zhang, Q., Gui, B., Fan, X., Chen, R., et al. (2019) · American Journal of Medical Genetics Part C Seminars in Medical Genetics · doi:10.1002/ajmg.c.31698 · Cited by 31
“…has been implicated in the formation of topologically associated domains (TADs) by binding to tens of thousands of DNA sequence- specific sites (CTCF motifs) in the human genome (Barutcu, Lian, Stein, Stein, & Imbalzano, 2017; Barutcu, Maass, Lewandowski, Weiner, & Rinn, 2018; Nora et al., 2017).”
BackgroundStructure–function relationships explain CTCF zinc finger mutation phenotypes in cancer
Bailey, C. G., Gupta, S. K., Metierre, C., Amarasekera, P. M. S., O’Young, P., Kyaw, W., Laletin, T., Francis, H., Semaan, C., Tabar, M. S., et al. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03946-z · Cited by 31
Dynamic Runx1 chromatin boundaries affect gene expression in hematopoietic development
Owens, D. D. G., Anselmi, G., Oudelaar, A. M., Downes, D. J., Cavallo, A., Harman, J. R., Schweßinger, R., Bucakci, A., Greder, L. V., Ornellas, S. D., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-28376-8 · Cited by 33
“Although studies in cell lines indicate that CTCF sites are required for TAD formation (Nora et al. 2017, Rao et al. 2017, Schwarzer et al. 2017, Wutz et al. 2017), interestingly, promoter-proximal CTCF sites have been suggested to play a role in E-P interactions and gene transcription (Canzio et…”
BackgroundCTCF: A misguided jack-of-all-trades in cancer cells
Segueni, J., & Noordermeer, D. (2022) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2022.05.044 · Cited by 31
“Combinations of biophysical modeling and experimental studies where CTCF, the cohesin complex subunit RAD21 or the cohesin loading factor NIPBL were depleted from the DNA have revealed that TADs are formed through a process of loop extrusion [66– 70].”
BackgroundAndreu, M. J., Alvarez-Franco, A., Portela, M., Giménez-Llorente, D., Cuadrado, A., Badía-Careaga, C., Tiana, M., Losada, A., & Manzanares, M. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111501 · Cited by 33
Gualdrini, F., Polletti, S., Simonatto, M., Prosperini, E., Pileri, F., & Natoli, G. (2022) · Genes & Development · doi:10.1101/gad.349282.121 · Cited by 35
“A well-known conundrum is the discrepancy between the large effects of CTCF or cohesin subunit loss on interphase genome folding on the one hand and the overall lowmagnitude effects on gene regulation on the other (Nora et al. 2017).”
Backgroundp53 rapidly restructures 3D chromatin organization to trigger a transcriptional response
Serra, F., Nieto-Aliseda, A., Fanlo, L., Rovirosa, L., Cabrera-Pasadas, M., Lazarenkov, A., Urmeneta, B., Alcalde-Merino, A., Nola, E., Okorokov, A. L., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-46666-1 · Cited by 30
“Therefore, cohesin degradation leads to rapid disappearance of TADs, antagonizes compartment segregation and promotes loss of most of the signi fi cant promoter-anchored interactions over ∼ 50Kb of length 10,13 – 22 .”
BackgroundAcute depletion of BRG1 reveals its primary function as an activator of transcription
Ren, G., Ku, W. L., Ge, G.-Z., Hoffman, J. A., Kang, J. Y., Tang, Q.-S., Cui, K.-R., He, Y., Guan, Y., Gao, B., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-48911-z · Cited by 32
Li, H., Dalgleish, J. L. T., Lister, G., Maristany, M. J., Huertas, J., Dopico-Fernandez, A. M., Hamley, J. C., Denny, N., Bloye, G., Zhang, W., et al. (2025) · Cell · doi:10.1016/j.cell.2025.10.013 · Cited by 35
Cohesin: building loops, but not compartments
Haarhuis, J. H. I., & Rowland, B. D. (2017) · The EMBO Journal · doi:10.15252/embj.201798654 · Cited by 27
“They show that CTCF is required for the formation of loops between CTCF sites (Fig 1A; Nora et al , 2017; Wutz et al , 2017).”
Irregular Chromatin: Packing Density, Fiber Width, and Occurrence of Heterogeneous Clusters
Bajpai, G., & Padinhateeri, R. (2019) · Biophysical Journal · doi:10.1016/j.bpj.2019.11.004 · Cited by 31
Sundararajan, V., Pang, Q. Y., Choolani, M. A., & Huang, R. Y. (2020) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2020.00213 · Cited by 29
Three-dimensional chromatin organization in cardiac development and disease
Bertero, A., & Rosa‐Garrido, M. (2020) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2020.11.008 · Cited by 32
“, who used an auxin-inducible degron system to demonstrate that while Ctcf is essential for TAD integrity in mouse embryonic stem cells, TAD integrity is maintained with as low as 4% of normal Ctcf expression [134].”
MethodSuper-Enhancers and CTCF in Early Embryonic Cell Fate Decisions
Agrawal, P., & Rao, S. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.653669 · Cited by 29
Ing‐Simmons, E., Rigau, M., & Vaquerizas, J. M. (2022) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2021.12.004 · Cited by 33
Predicting genome organisation and function with mechanistic modelling
Chiang, M., Brackley, C. A., Marenduzzo, D., & Gilbert, N. (2021) · Trends in Genetics · doi:10.1016/j.tig.2021.11.001 · Cited by 35
“Domains are also affected by degradation of CTCF [44], cohesin [45,46], and complexes involved in cohesin loading and unloading [47,48].”
InfluentialErosion of the Epigenetic Landscape and Loss of Cellular Identity as a Cause of Aging in Mammals
Yang, J.-H., Griffin, P. T., Vera, D. L., Apostolides, J. K., Hayano, M., Meer, M. V., Salfati, E. L., Su, Q., Munding, E. M., Blanchette, M., et al. (2019) · doi:10.1101/808642 · Cited by 38
“We speculate that changes to histone modifications in ICE cells precede changes in CTCF binding and TADs, but ultimately they are disrupted due to a positive feedback loop driven perhaps by a loss of histones and increased susceptibility to DNA damage, causing cells to eventually senesce, even if they are non-dividing…”
BackgroundInfluentialSynergy between regulatory elements can render cohesin dispensable for distal enhancer function
Hansen, K. L., Adachi, A. S., Braccioli, L., Kadvani, S., Boileau, R. M., Martinovic, M., Pokorny, B., Shah, R., Anderson, E. C., Zhang, K., et al. (2026) · Science · doi:10.1126/science.adt4221 · Cited by 29
Self-citationRec8 Cohesin-mediated Axis-loop chromatin architecture is required for meiotic recombination
Sakuno, T., Tashiro, S., Tanizawa, H., Iwasaki, O., Ding, D., Haraguchi, T., Noma, K.-I., & Hiraoka, Y. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac183 · Cited by 29
Three-dimensional chromatin architecture in plants – General features and novelties
Tourdot, É., & Grob, S. (2023) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2023.151344 · Cited by 29
Cell type–specific 3D-genome organization and transcription regulation in the brain
Liu, S., Wang, C. Y., Zheng, P., Jia, B. B., Zemke, N. R., Ren, P., Park, H. L., Ren, B., & Zhuang, X. (2025) · Science Advances · doi:10.1126/sciadv.adv2067 · Cited by 34
Maksimenko, O. G., Kyrchanova, O., Klimenko, N. S., Zolotarev, N., Elizarova, A., Bonchuk, A. N., & Georgiev, P. G. (2019) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2019.194446 · Cited by 30
Differential 3D chromatin organization and gene activity in genomic imprinting.
Noordermeer, D., & Feil, R. (2020) · Current Opinion in Genetics and Development · doi:10.1016/j.gde.2020.03.004 · Cited by 25
“Depletion of 113 CTCF or Cohesin components results in the loss of domain organization, confirming their 114 essential roles in structuring (sub-)TADs [38,39].”
BackgroundG-quadruplex binding protein Rif1, a key regulator of replication timing
Alavi, S., Ghadiri, H., Dabirmanesh, B., Moriyama, K., Khajeh, K., & Masai, H. (2020) · The Journal of Biochemistry · doi:10.1093/jb/mvaa128 · Cited by 29
Dynamic regulation of CTCF stability and sub-nuclear localization in response to stress
Lehman, B. J., López-Díaz, F. J., Santisakultarm, T. P., Fang, L., Shokhirev, M. N., Diffenderfer, K. E., Manor, U., & Emerson, B. M. (2021) · PLoS Genetics · doi:10.1371/journal.pgen.1009277 · Cited by 30
“Another study, also using degron-mediated degradation of CTCF in mouse ESCs, showed that CTCF looping and insulation of TADs is dependent upon CTCF protein abundance whereas active and inactive genome compartments remained stable even when CTCF was depleted [85].”
BackgroundRNA helicase-dependent gene looping impacts messenger RNA processing
Terrone, S., Valat, J., Fontrodona, N., Giraud, G., Claude, J., Combe, E., Lapendry, A., Polvèche, H., Ameur, L. B., Duvermy, A., et al. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac717 · Cited by 29
CTCF blocks antisense transcription initiation at divergent promoters
Luan, J. Y., Vermunt, M. W., Syrett, C. M., Coté, A., Tome, J. M., Zhang, H., Huang, A., Luppino, J. M., Keller, C. A., Giardine, B. M., et al. (2022) · Nature Structural & Molecular Biology · doi:10.1038/s41594-022-00855-y · Cited by 29
A spatial genome aligner for resolving chromatin architectures from multiplexed DNA FISH
Jia, B. B., Jussila, A., Kern, C., Zhu, Q., & Ren, B. (2023) · Nature Biotechnology · doi:10.1038/s41587-022-01568-9 · Cited by 30
Auxin-Inducible Degron System: An Efficient Protein Degradation Tool to Study Protein Function
Phanindhar, K., & Mishra, R. K. (2023) · BioTechniques · doi:10.2144/btn-2022-0108 · Cited by 30
Perturb-tracing enables high-content screening of multi-scale 3D genome regulators
Cheng, Y., Hu, M., Yang, B., Jensen, T. B., Zhang, Y., Yang, T., Yu, R., Ma, Z., Radda, J. S. D., Jin, S., et al. (2025) · Nature Methods · doi:10.1038/s41592-025-02652-z · Cited by 31
“These positive control results are consistent with the opposing roles of CTCF and NIPBL in loop extrusion 2–4, 27, 28 and We next explored the regulation of chromatin folding conformations at the length scale of A–”
Korkmaz, G., Manber, Z., Lopes, R., Preković, S., Schuurman, K. G., Kim, Y., Teunissen, H., Flach, K. D., de Wit, E., Galli, G. G., et al. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz675 · Cited by 29
“used an auxin-inducible degron system to elaborate the role of CTCF in gene regulation and organization of chromatin structure by triggering acute CTCF degradation (76).”
MethodLoop formation by SMC complexes: turning heads, bending elbows, and fixed anchors
Sedeño Cacciatore, Á., & Rowland, B. D. (2019) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2019.04.010 · Cited by 24
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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