CTCF confers local nucleosome resiliency after DNA replication and during mitosis

Owens, Nick; Papadopoulou, Thaleia; Festuccia, Nicola; Tachtsidi, Alexandra; González, Inma; Dubois, Agnès; Vandormael-Pournin, Sandrine; Nora, Elphège P.; Bruneau, Benoit G.; Cohen-Tannoudji, Michel; Navarro, Pablo

doi:10.7554/elife.47898

Cited by 75 publications

(127 citation statements)

References 78 publications

(159 reference statements)

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“…Secondly, we found that the NRL decrease near CTCF is correlated with CTCF-DNA binding affinity ( Figure 1D and 5F). This result goes significantly beyond previous observations that the CTCF binding strength is related to a more regular nucleosome ordering near its binding site (43,65) and may have direct functional implications.…”

Section: Discussionsupporting

confidence: 43%

CTCF-dependent chromatin boundaries formed by asymmetric nucleosome arrays with decreased linker length

Clarkson

Deeks

Samarista

et al. 2019

Preprint

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The CCCTC-binding factor (CTCF) organises the genome in 3D through DNA loops and in 1D by setting boundaries isolating different chromatin states, but these processes are not well understood. Here we focus on the relationship between CTCF binding and the decrease of the Nucleosome Repeat Length (NRL) for ~20 adjacent nucleosomes, affecting up to 10% of the mouse genome. We found that the chromatin boundary near CTCF is created by the nucleosome-depleted region (NDR) asymmetrically located >40 nucleotides 5'-upstream from the centre of CTCF motif. The strength of CTCF binding to DNA is correlated with the decrease of NRL near CTCF and anti-correlated with the level of asymmetry of the nucleosome array. Individual chromatin remodellers have different contributions, with Snf2h having the strongest effect on the NRL decrease near CTCF and Chd4 playing a major role in the symmetry breaking. Upon differentiation of embryonic stem cells to neural progenitor cells and embryonic fibroblasts, a subset of common CTCF sites preserved in all three cell types maintains a relatively small local NRL despite genome-wide NRL increase. The sites which lost CTCF upon differentiation are characterised by nucleosome rearrangement 3'-downstream, but the boundary defined by the NDR 5'-upstream of CTCF motif remains.

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Section: Discussionsupporting

confidence: 43%

CTCF-dependent chromatin boundaries formed by asymmetric nucleosome arrays with decreased linker length

Clarkson

Deeks

Samarista

et al. 2019

Preprint

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“…The architectural protein CTCF insulates adjacent active and repressed chromatin domains and also mediates 3-D contacts at several developmentally regulated genomic loci (Cuddapah et al, 2009;Fu et al, 2008;Narendra et al, 2015;Phillips and Corces, 2009) Owens et al, 2019, Clarkson et al, 2019. In addition to precisely mapping direct transcription factor footprints, CUT&RUN also probes the local and 3-D chromatin environments around CTCF binding sites (Skene and Henikoff, 2017).…”

Section: Discussionmentioning

confidence: 99%

Architectural RNA is required for heterochromatin organization

Thakur

Llagas

et al. 2019

Preprint

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In addition to its known roles in protein synthesis and enzyme catalysis, RNA has been proposed to stabilize higher-order chromatin structure. To distinguish presumed architectural roles of RNA from other functions, we applied a ribonuclease digestion strategy to our CUT&RUN in situ chromatin profiling method (CUT&RUN.RNase). We find that depletion of RNA compromises association of the murine nucleolar protein Nucleophosmin with pericentric heterochromatin and alters the chromatin environment of CCCTC-binding factor (CTCF) bound regions. Strikingly, we find that RNA maintains the integrity of both constitutive (H3K9me3 marked) and facultative (H3K27me3 marked) heterochromatic regions as compact domains, but only moderately stabilizes euchromatin. To establish the specificity of heterochromatin stabilization by RNA, we performed CUT&RUN on cells deleted for the Firre long non-coding RNA and observed disruption of H3K27me3 domains on several chromosomes. We conclude that RNA maintains local and global chromatin organization by acting as a structural scaffold for heterochromatic domains.1

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“…5a). Prior reports have described varying degrees of CTCF mitotic retention 20,21,22 . This observation was confirmed by ChIP-qPCR at individual CTCF binding sites (Extended Data Fig.…”

Section: Main Textmentioning

confidence: 95%

Re-configuration of Chromatin Structure During the Mitosis-G1 Phase Transition

Zhang

et al. 2019

Preprint

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14Higher-order chromatin organization such as A/B compartments, TADs and chromatin loops are 15 temporarily disrupted during mitosis. These structures are thought to organize aspects of gene 16 regulation, and thus it is important to understand how they are re-established after mitosis. We 17 examined the dynamics of chromosome reorganization by Hi-C at defined time points following 18 exit from mitosis in highly purified, synchronous cell populations. We observed that A/B 19 compartments are rapidly established and progressively gain in strength following mitotic exit. 20Contact domain formation occurs from the "bottom-up" with smaller sub-TADs forming initially, 21 followed by convergence into multi-domain TAD structures. CTCF is strongly retained at a 22 that ana/telophase cells display significantly reduced compartmentalization between genomic 64 regions separated by >12Mb (Extended Data Fig. 3h). However, higher levels of 65 compartmentalization are observed between more distal (>100Mb) genomic regions after G1 entry 66 (Extended Data Fig. 3h, i), confirming that compartmentalization expands throughout the entire 67 chromosome after mitosis. In summary, a major re-configuration of genome structure occurs 68 during the pro-M-G1 transition, with a rapid establishment, progressive strengthening, and 69 expansion of A/B compartments throughout the genome (Extended Data Fig. 1a). 70 71 Next, we examined formation after mitosis of TADs and nested sub-TADs 11,12 using 3DNetMod 72 13 . We identified 8073 contact domains progressively gained from pro-metaphase to mid-G1 ( Fig. 73 1b, Extended Data Fig. 4b, Extended Data Table3). We observed gradually increased insulation at 74 domain boundaries, suggesting strengthening of TADs over time (Extended Data Fig. 4a). 75Previous studies reported complete loss of domains in pro-metaphase 2,3,7 . However, notably, 76 despite significant attenuation of signal, residual domain-like structures are still qualitatively and 77 algorithmically detectable in pro-metaphase cells (Extended Data Fig. 4c). The presence of pro-78 metaphase TAD/subTADs is unlikely due to contamination from interphase cells given the high 79 purity of our mitotic preps and the fact that these residual structures are not homogenously 80 distributed across the genome (Extended Data Fig. 4c). Thus, pro-metaphase is not prohibitive to 81 the maintenance of chromatin structures. 82 83 Formation of TADs may occur via convergence of previously emerged sub-TADs (bottom-up), 84 the partitioning of initially formed TADs into sub-TADs (top-down), or simultaneous birth of both 85 contact domain types (Extended Data Fig. 4d). On average, contact domains called at time points 86 later in G1 are larger than those called at preceding cell stages. (Fig. 1b, c). In addition, an average 87 of ~1.5 boundaries per domain are found at pro-metaphase, whereas only ~0.58 boundary is created 88 per domain in mid-G1 ( Fig. 1d), suggesting that boundaries are being shared between sequentially 89 formed domains. These results support...

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CTCF confers local nucleosome resiliency after DNA replication and during mitosis

Cited by 75 publications

References 78 publications

CTCF-dependent chromatin boundaries formed by asymmetric nucleosome arrays with decreased linker length

CTCF-dependent chromatin boundaries formed by asymmetric nucleosome arrays with decreased linker length

Architectural RNA is required for heterochromatin organization

Re-configuration of Chromatin Structure During the Mitosis-G1 Phase Transition

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