The mitotic STAG3-cohesin complex shapes male germline nucleome [single-cell RNA-seq]

Germ cells are unique in that they tailor chromatin toward generating totipotency. Accordingly, mammalian spermatogonia, including spermatogonial stem cells (SSCs) which constitute the source for male gametes, acquire distinctive chromatin organization with weak insulation, but the underlying mechanism remains unknown. Here, we show that STAG3, this far known to exclusively form meiotic cohesins, generates a mitotic cohesin for male germline nucleome programming in mice. Due to its shorter chromatin residence, STAG3cohesin attenuates topologically associating domains (TADs), rewires enhancerpromoter and Polycomb-mediated repressive interactions, and facilitates finer and more strengthened compartments, establishing a distinctive spermatogonial nucleome. Moreover, in the absence of STAG3cohesin, SSCs show an impaired differentiation priming for spermatogenesis. Mitotic STAG3cohesin is also expressed in human B cells and their malignant variations, promoting their propagation. Our findings on mitotic STAG3cohesin elucidate a principle of male germline nucleome programming, demonstrate an unexpected mitotic role for STAG3 and might potentially improve understanding of human malignancies. 10X Genomics scRNA-seq生殖细胞的独特之处在于其可重塑染色质以产生全能性。据此，哺乳动物精原细胞——包括作为雄性配子来源的精原干细胞（spermatogonial stem cells, SSCs）——会形成具有弱绝缘特性的独特染色质组织模式，但其潜在调控机制仍未明确。本研究表明，此前被认为仅参与组装减数分裂黏连蛋白的STAG3，可在小鼠体内形成一种有丝分裂型黏连蛋白，介导雄性生殖系核编程。由于其染色质驻留时长更短，STAG3黏连复合体（STAG3cohesin）可弱化拓扑关联结构域（topologically associating domains, TADs）的结构，重编程增强子-启动子与多梳蛋白（Polycomb）介导的抑制性相互作用，并促成更精细且更稳固的染色质区室，从而构建出独特的精原细胞核组。此外，当STAG3黏连复合体缺失时，精原干细胞的精子发生相关分化启动能力会受损。有丝分裂型STAG3黏连复合体在人类B细胞及其恶性转化细胞中也有表达，并可促进这些细胞的增殖。本研究关于有丝分裂型STAG3黏连复合体的发现，阐明了雄性生殖系核编程的一项核心原则，揭示了STAG3此前未被认知的有丝分裂功能，或有助于加深对人类恶性肿瘤的理解。10X Genomics scRNA-seq