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

Abstract

The distribution of cohesin in the mouse genome depends on CTCF, transcription and the cohesin release factor Wapl. Cohesin and CTCF are known to spatially organize mammalian genomes into chromatin loops and topologically associated domains. CTCF binds to specific DNA sequences, but it is unclear how cohesin is recruited to these sites. Here, Jan-Michael Peters and colleagues show that the distribution of cohesin in the mouse genome depends on CTCF, transcription and the cohesin-release factor Wapl. In the absence of CTCF, cohesin accumulates at the transcription start sites of active genes, which are bound by the cohesion-loading complex. In the absence of both CTCF and Wapl, cohesin accumulates at the 3′ end of active genes. The authors propose that cohesin is loaded onto DNA at sites that are distinct from its final binding sites and can be translocated by transcription until it either encounters CTCF bound to DNA or is released by Wapl. A mechanism of transcription-mediated cohesin translocation could allow the extrusion of chromatin loops. Mammalian genomes are spatially organized by CCCTC-binding factor (CTCF) and cohesin into chromatin loops1,2 and topologically associated domains3,4,5,6, which have important roles in gene regulation1,2,4,5,7 and recombination7,8,9. By binding to specific sequences10, CTCF defines contact points for cohesin-mediated long-range chromosomal cis-interactions1,2,4,5,6,7,11. Cohesin is also present at these sites12,13, but has been proposed to be loaded onto DNA elsewhere14,15 and to extrude chromatin loops until it encounters CTCF bound to DNA16,17,18,19. 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 located14,15. 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 cohesin20,21,22,23, 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.