An RNA-binding region regulates CTCF clustering and chromatin looping

Hansen, Anders S.; Ts, Hsieh; Cattoglio, Claudia; Pustova, Iryna; Darzacq, Xavier; Tjian, Robert

doi:10.1101/495432

Cited by 18 publications

(31 citation statements)

References 80 publications

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“…Finally, it is tempting to speculate a connection between our identified clusters of closely located CTCF binding sites on the genome and the reportedly observed 3D "clusters" (or "hubs") of CTCF protein molecules (Hansen et al, 2018b(Hansen et al, , 2018c. In particular, Hansen et al have proposed a guided mechanism where an RNA strand can bind to and gather together multiple CTCF protein molecules near cognate binding sites.…”

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confidence: 68%

“…In particular, Hansen et al have proposed a guided mechanism where an RNA strand can bind to and gather together multiple CTCF protein molecules near cognate binding sites. These CTCF molecule hubs apparently enhance the search 15 for target binding sites, increase the binding rate of CTCF to its related sites (also as part of the LMC model) and are often implicated in chromatin loop formation (Hansen et al, 2018b(Hansen et al, , 2018c. It is possible that our identified CTCF site clusters act synergistically with this mechanism as nearby sites for the concentrated CTCF molecules to bind.…”

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confidence: 86%

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Clustered CTCF binding is an evolutionary mechanism to maintain topologically associating domains

Kentepozidou

Aitken

Feig

et al. 2019

Preprint

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CTCF binding contributes to the establishment of higher order genome structure by demarcating the boundaries of large-scale topologically associating domains (TADs). We have carried out an experimental and computational study that exploits the natural genetic variation across five closely related species to assess how CTCF binding patterns stably fixed by evolution in each species 5 contribute to the establishment and evolutionary dynamics of TAD boundaries. We performed CTCF ChIP-seq in multiple mouse species to create genome-wide binding profiles and associated them with TAD boundaries. Our analyses reveal that CTCF binding is maintained at TAD boundaries by an equilibrium of selective constraints and dynamic evolutionary processes. Regardless of their conservation across species, CTCF binding sites at TAD boundaries are 10 subject to stronger sequence and functional constraints compared to other CTCF sites. TAD boundaries frequently harbor rapidly evolving clusters containing both evolutionary old and young CTCF sites as a result of repeated acquisition of new species-specific sites close to conserved ones. The overwhelming majority of clustered CTCF sites colocalize with cohesin and are significantly closer to gene transcription start sites than nonclustered CTCF sites, suggesting that 15 CTCF clusters particularly contribute to cohesin stabilization and transcriptional regulation. Overall, CTCF site clusters are an apparently important feature of CTCF binding evolution that are critical the functional stability of higher order chromatin structure.

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confidence: 68%

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confidence: 86%

Clustered CTCF binding is an evolutionary mechanism to maintain topologically associating domains

Kentepozidou

Aitken

Feig

et al. 2019

Preprint

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“…4D-E and fig. S8C)(31). In contrast, Pol II and active histone modifications mark robust short-range boundaries but are associated with weaker long-range insulators compared to CTCF/cohesin (Fig.…”

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confidence: 95%

Resolving the 3D landscape of transcription-linked mammalian chromatin folding

Slobodyanyuk

Hansen

et al. 2019

Preprint

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118

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Chromatin folding below the scale of topologically associating domains (TADs) remains largely unexplored in mammals. Here, we used a high-resolution 3C-based method, Micro-C, to probe links between 3D-genome organization and transcriptional regulation in mouse stem cells. 20Combinatorial binding of transcription factors, cofactors, and chromatin modifiers spatially segregate TAD regions into "microTADs" with distinct regulatory features. Enhancer-promoter and promoter-promoter interactions extending from the edge of these domains predominantly link co-regulated loci, often independently of CTCF/Cohesin. Acute inhibition of transcription disrupts the gene-related folding features without altering higher-order chromatin structures. 25Intriguingly, we detect "two-start" zig-zag 30-nanometer chromatin fibers. Our work uncovers the finer-scale genome organization that establishes novel functional links between chromatin folding and gene regulation. 30ONE SENTENCE SUMMARY Transcriptional regulatory elements shape 3D genome architecture of microTADs. MAIN TEXT 35Chromatin packages the eukaryotic genome via a hierarchical series of folding steps ranging from nucleosomes to chromosome territories (1). Structural analysis of chromosome folding has been revolutionized by the Chromosome Conformation Capture (3C) family of techniques, which uses proximity ligation of cross-linked genomic loci in vivo to estimate contact frequencies (2). Interphase chromosome structures such as compartments (3), topologically-40 associating domains (TADs) (4, 5), and CTCF/cohesin chromatin loops (6) have been characterized using 3C-based methods. Chromosome compartments correspond to large-scale active and inactive chromatin segments and appear as a plaid-like pattern in Hi-C contact maps at the megabase scale (3). At the intermediate scale of tens to hundreds of kilobases, topologically associating domains (TADs) spatially organize the mammalian genome into 45 continuous self-interacting domains. TADs are defined as local domains in which genomic loci contact each other more frequently within the domain than with loci outside. TADs appear as square boxes along the diagonal of 3D contact maps (4, 5). Mounting evidence suggests that CTCF and cohesin likely mediate TAD formation via a loop extrusion mechanism (7, 8) wherein the cohesin ring complex entraps chromatin loci and extrudes chromatin until blocked by CTCF 50 or other proteins. Stabilization of cohesin at CTCF sites result in sharp corner peaks in contact maps and are also referred to as CTCF/cohesin loops or loop domains. Various studies have

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“…Recently, we found that the maternal expression of Meg3, and possibly the lncRNA itself, prevents activation of Dlk1 as well (25). We hypothesise that the two mechanisms are linked, with either the Dlk1-Meg3 sub-TAD focusing or constraining the repressive function of the Meg3 expression or transcript, or conversely, with maternal Meg3 expression facilitating CTCF recruitment or its stability of binding at the DMR, possibly through direct RNA-CTCF contacts (32,33).…”

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confidence: 90%

CTCF controls imprinted gene activity at the mouseDlk1-Dio3andIgf2-H19domains by modulating allele-specific sub-TAD structure

Llères

Moindrot

Pathak

et al. 2019

Preprint

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Mammalian genomic imprinting is essential for development and provides a unique paradigm to explore intra-cellular differences in chromatin configuration. Here, we compared chromatin structure of the two conserved imprinted domains controlled by paternal DNA methylation imprints-the Igf2-H19 and the Dlk1-Dio3 domains-and assessed the involvement of the insulator protein CTCF. At both domains, CTCF binds the maternal allele of a differentiallymethylated region (DMR), in addition to multiple instances of bi-allelic CTCF binding in their surrounding TAD (Topologically Associating Domain). On the paternal chromosome, bi-allelic CTCF binding alone is sufficient to structure a first level of sub-TAD organization. Maternal-specific CTCF binding at the DMRs adds a further layer of sub-TAD organization, which essentially hijacks the existing paternal sub-TAD organisation. Genome-editing experiments at the Dlk1-Dio3 locus confirm that the maternal sub-TADs are essential during development to maintain the imprinted Dlk1 gene in an inactive state on the maternal chromosome.

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An RNA-binding region regulates CTCF clustering and chromatin looping

Cited by 18 publications

References 80 publications

Clustered CTCF binding is an evolutionary mechanism to maintain topologically associating domains

Clustered CTCF binding is an evolutionary mechanism to maintain topologically associating domains

Resolving the 3D landscape of transcription-linked mammalian chromatin folding

CTCF controls imprinted gene activity at the mouseDlk1-Dio3andIgf2-H19domains by modulating allele-specific sub-TAD structure

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