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, STAG3–cohesin attenuates topologically associating domains (TADs), rewires enhancer–promoter and Polycomb-mediated repressive interactions, and facilitates finer and more strengthened compartments, establishing a distinctive spermatogonial nucleome. Moreover, in the absence of STAG3–cohesin, SSCs show an impaired differentiation priming for spermatogenesis. Mitotic STAG3–cohesin is also expressed in human B cells and their malignant variations, promoting their propagation. Our findings on mitotic STAG3–cohesin 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

生殖细胞的独特性在于其可通过重塑染色质以产生全能性。包括作为雄性配子来源的精原干细胞（spermatogonial stem cells, SSCs）在内的哺乳动物精原细胞，会形成具有弱绝缘特性的独特染色质结构，但其背后的潜在分子机制仍未明确。本研究发现，此前被认为仅参与组成减数分裂黏连蛋白复合体的STAG3，在小鼠体内可形成一种有丝分裂黏连蛋白复合体，用于调控雄性生殖系核编程。由于该复合体的染色质驻留时间更短，STAG3黏连蛋白复合体可弱化拓扑关联结构域（TADs），重塑增强子-启动子与多梳蛋白介导的抑制性相互作用网络，并促成更精细且更强化的染色质区室结构，从而构建出独特的精原细胞核组。此外，当STAG3黏连蛋白复合体缺失时，精原干细胞的精子发生分化启动潜能会受损。有丝分裂型STAG3黏连蛋白复合体在人类B细胞及其恶性变异株中也有表达，可促进细胞增殖。我们关于有丝分裂型STAG3黏连蛋白复合体的研究结果阐明了雄性生殖系核编程的一项核心原则，揭示了STAG3此前未被发现的有丝分裂功能，或有助于增进对人类恶性肿瘤的认知。本研究采用10X Genomics单细胞RNA测序（10X Genomics scRNA-seq）技术。