Cohesin is positioned in mammalian genomes by transcription, CTCF and Wapl

Abstract

Mammalian genomes are spatially organized by CCCTC-binding factor (CTCF) and cohesin into chromatin loops and topologically associated domains, which have important roles in gene regulation and recombination. By binding to specific sequences, CTCF defines contact points for cohesin-mediated long-range chromosomal cis-interactions. Cohesin is also present at these sites, but has been proposed to be loaded onto DNA elsewhere and to extrude chromatin loops until it encounters CTCF bound to DNA. How cohesin is recruited to CTCF sites, according to this or other models, is unknown. Here we show that the distribution of cohesin in the mouse genome depends on transcription, CTCF and the cohesin release factor Wings apart-like (Wapl). In CTCF-depleted fibroblasts, cohesin cannot be properly recruited to CTCF sites but instead accumulates at transcription start sites of active genes, where the cohesin-loading complex is located. In the absence of both CTCF and Wapl, cohesin accumulates in up to 70 kilobase-long regions at 3'-ends of active genes, in particular if these converge on each other. Changing gene expression modulates the position of these 'cohesin islands'. These findings indicate that transcription can relocate mammalian cohesin over long distances on DNA, as previously reported for yeast cohesin, that this translocation contributes to positioning cohesin at CTCF sites, and that active genes can be freed from cohesin either by transcription-mediated translocation or by Wapl-mediated release.

Group 1 Innate Lymphoid Cell Lineage Identity Is Determined by a cis-Regulatory Element Marked by a Long Non-coding RNA

“…Cohesin promotes the extrusion of chromatin loops until it encounters CTCF bound to DNA (Merkenschlager and Nora, 2016). While CTCF binds specific DNA sequences, recent evidence indicates that transcription significantly contributes to positioning cohesin in the mammalian genome (Busslinger et al, 2017). Here we showed that the Rroid locus and Id2 promoter interact with each other through a long-range chromatin loop.…”

ESCO1/2's roles in chromosome structure and interphase chromatin organization

“…These differences are likely caused at least in part by the fact that DT40 and U2OS cells are dividing cells, and cohesin spends less time on chromatin before its removal by separase. We conclude that distinct model systems lead to differently appearing chromosome territories, the morphology of which may also vary based on the cohesin subunit that is analyzed (SMC3 here vs. SCC1 in previous studies) (Tedeschi et al 2013;Busslinger et al 2017;Haarhuis et al 2017).…”

“…WAPL is important for the organization of cohesin-defined chromosome territories, as observed in post-mitotic MEFs and haploid human cell lines mutated in WAPL (Tedeschi et al 2013;Busslinger et al 2017;Haarhuis et al 2017). When we analyzed the pattern of cohesin staining in DT40 interphase cells (6 h after WAPL depletion) (see Fig.…”

Twenty-First Century Glucocorticoid Receptor Molecular Biology

“…Cohesin rings are composed of the core subunits SMC1, SMC3, RAD21, and STAG [58,59]. Cohesin is most likely loaded onto its chromatid substrate by the NIPBL2/Mau2 cohesin-loading complex, which is enriched at transcription start sites (TSS) [60,61]. Conversely, cohesin release from chromatids is facilitated by WAPL [62].…”

“…Indeed, while inhibiting cohesin loading (by inhibiting cohesin loading factors) inhibits the formation of topologically associated domains, inhibiting cohesin release by inhibiting WAPL restricts loop extension [64]. In the absence of both CTCF and WAPL, cohesin accumulates in up to 70 kilobase-long regions at the 3′-ends of active genes, in particular, if these converge on each other [60,61].…”