Journal
EMBO JOURNAL
Volume 36, Issue 24, Pages 3573-3599Publisher
WILEY
DOI: 10.15252/embj.201798004
Keywords
chromatin condensation; chromatin structure; genome organization; loop extrusion; vermicelli
Categories
Funding
- Boehringer Ingelheim
- Austrian Science Fund (FWF special research program) [SFB F34]
- Austrian Science Fund (Wittgenstein award) [Z196-B20]
- Austrian Research Promotion Agency [FFG-834223]
- UK Biotechnology and Biological Sciences Research Council [BB/J004480/1]
- European Research Council Advanced Grant (DEVOCHROMO)
- EMBO Long Term Fellowship [ALTF 1335-2016]
- HFSP [LT001527/2017]
- 4D Nucleome/4DN NIH Common Fund [U01 EB021223]
- European Molecular Biology Laboratory
- EMBL International PhD Programme
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Mammalian genomes are spatially organized into compartments, topologically associating domains (TADs), and loops to facilitate gene regulation and other chromosomal functions. How compartments, TADs, and loops are generated is unknown. It has been proposed that cohesin forms TADs and loops by extruding chromatin loops until it encounters CTCF, but direct evidence for this hypothesis is missing. Here, we show that cohesin suppresses compartments but is required for TADs and loops, that CTCF defines their boundaries, and that the cohesin unloading factor WAPL and its PDS5 binding partners control the length of loops. In the absence of WAPL and PDS5 proteins, cohesin forms extended loops, presumably by passing CTCF sites, accumulates in axial chromosomal positions (vermicelli), and condenses chromosomes. Unexpectedly, PDS5 proteins are also required for boundary function. These results show that cohesin has an essential genome-wide function in mediating long-range chromatin interactions and support the hypothesis that cohesin creates these by loop extrusion, until it is delayed by CTCF in a manner dependent on PDS5 proteins, or until it is released from DNA by WAPL.
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