The Cohesin Release Factor WAPL Restricts Chromatin Loop Extension

TLDR

Chromosome spatial organization, governed by cohesin-mediated looping of CTCF sites, influences nuclear processes such as gene expression. Our data show that WAPL limits chromatin loop extension and prevents misoriented CTCF interactions, while the SCC2/SCC4 complex promotes loop enlargement and TAD formation, indicating that balanced SCC2/SCC4 and WAPL activity is essential for proper chromosome architecture and limits nuclear compartmentalization.

Abstract

The spatial organization of chromosomes influences many nuclear processes including gene expression. The cohesin complex shapes the 3D genome by looping together CTCF sites along chromosomes. We show here that chromatin loop size can be increased and that the duration with which cohesin embraces DNA determines the degree to which loops are enlarged. Cohesin's DNA release factor WAPL restricts this loop extension and also prevents looping between incorrectly oriented CTCF sites. We reveal that the SCC2/SCC4 complex promotes the extension of chromatin loops and the formation of topologically associated domains (TADs). Our data support the model that cohesin structures chromosomes through the processive enlargement of loops and that TADs reflect polyclonal collections of loops in the making. Finally, we find that whereas cohesin promotes chromosomal looping, it rather limits nuclear compartmentalization. We conclude that the balanced activity of SCC2/SCC4 and WAPL enables cohesin to correctly structure chromosomes.