GSE132264
Wapl-mediated release of Scc1-cohesin regulates chromosome structure and segregation in mouse oocytes
Cohesin is essential for genome folding and chromosome inheritance through cell divisions. In somatic cells, both of these functions are mediated by Scc1-cohesin, which in mitosis is released from chromosomes by Wapl and separase. In mammalian oocytes, cohesion is mediated by Rec8-cohesin. Scc1 is also expressed but neither required nor sufficient for cohesion, and its function in oocytes is unknown. Likewise, it is unknown whether Wapl regulates one or both cohesin complexes and chromosome segregation in mature oocytes. Using conditional mouse mutagenesis, we show that in meiosis I Wapl is required for proper chromosome segregation, predominantly releases Scc1-cohesin from chromosomes and promotes production of euploid eggs. Using single-nucleus Hi-C, we found that Scc1 is essential for chromatin loops and topologically associating domains (TADs) in oocytes. Increasing Scc1 residence time on chromosomes by Wapl depletion leads to vermicelli formation and intra-loop structures but, unlike in mitotic cells, does not increase loop size. This implies that loop size has reached a maximum in oocytes, possibly because it is limited by barriers such as cohesive cohesin. We conclude that distinct cohesin complexes generate loops and cohesion in mammalian oocytes and propose that the same principle applies to all cell types and species. Overall design: We generated Scc1-control (Scc1fl/fl), Scc1-KO (Scc1?/?), Wapl-control (Waplfl/fl) and Wapl-KO (Wapl?/?) Hi-C libraries from single NSN and SN oocytes of 2-2.5 months old mice: Scc1fl/fl, Scc1fl/fl (Tg)Zp3-Cre, Waplfl/fl and Waplfl/fl (Tg)Zp3-Cre, respectively.  Number of oocytes analyzed and Hi-C libraries prepared: 21 NSN Scc1fl/fl oocytes, 17 SN Scc1fl/fl oocytes, 20 NSN Scc1?/? oocytes, 15 SN Scc1?/? oocytes, 12 NSN Waplfl/fl oocytes, 11 SN Waplfl/fl oocytes, 20 NSN Wapl?/? oocytes, 16 SN Wapl?/? oocytes.