Cohesin residency determines chromatin loop patterns

Abstract

The organization of chromatin into higher order structures is essential for chromosome segregation, the repair of DNA-damage, and the regulation of gene expression. Using Micro-C XL to detect chromosomal interactions, we observed the pervasive presence of cohesin-dependent loops with defined positions throughout the genome of budding yeast, as seen in mammalian cells. In early S phase, cohesin stably binds to cohesin associated regions (CARs) genome-wide. Subsequently, positioned loops accumulate with CARs at the bases of the loops. Cohesin regulators Wpl1 and Pds5 alter the levels and distribution of cohesin at CARs, changing the pattern of positioned loops. From these observations, we propose that cohesin with loop extrusion activity is stopped by preexisting CAR-bound cohesins, generating positioned loops. The patterns of loops observed in a population of wild-type and mutant cells can be explained by this mechanism, coupled with a heterogeneous residency of cohesin at CARs in individual cells.

Cohesin architecture and clustering in vivo

“…( C ) Peaks of cohesin clusters correlate with previously identified CAR sites. Anti-Mcd1p ChIP-seq trace ( Costantino et al, 2020 ) at chrIII was compared with ChIP-seq traces from Figure 5E . ( D ) ChIP-seq traces showing localization of cohesin clusters on chromosome I (top) and part of chromosome II (bottom).…”

“…We recently showed that cohesin forms positioned loops genome-wide in mid-M. These loops continue to form in cells depleted of Pds5p or expressing mcd1p-Q266 where cohesin clustering is blocked ( Costantino et al, 2020 ). The ability of these mutants to loop extrude but not to cluster suggests that cohesin clusters are not obligatory for loop extrusion in vivo.…”

RNA surveillance controls 3D genome structure via stable cohesin-chromosome interaction

“…Interestingly, these TAD-like structures and chromatin loops are also found in organisms that lack CTCF homologs. From S.cerevisiae to S.pombe, C.elegans, and A. thaliana, these organisms reveal discrete self-interacting domains with varying domain lengths independent of CTCF (Costantino et al, 2020;Hsieh et al, 2015;Rowley et al, 2017;Rowley and Corces, 2016). The cohesin, a ring-shaped protein complex, mediates the stable cohesion of sister chromatids and loop extrusion by holding distant DNA fragments in close spatial proximity (Murayama et al, 2018;Onn et al, 2008).…”

Cohesin Mutations in Cancer: Emerging Therapeutic Targets

“…The nucleolus is the hub of ribosome biogenesis, and aberrant nucleolar morphologies are observed in cohesin depleted models [78,80,81]. In yeast, during mitosis, cohesin was shown to be required for restricting chromatin contacts between rDNA repeats, and between rDNA and the rest of the genome [82]. Cohesin function in facilitating DNA replication appears to be essential for rRNA production and nucleolar integrity [79].…”