SCML2 Establishes the Male Germline Epigenome

Gametogenesis is dependent on the expression of germline-specific genes. However, it remains unknown how the germline epigenome is distinctly established from that of somatic lineages. Here we show that genes commonly expressed in somatic lineages and spermatogenesis-progenitor cells undergo repression in a genome-wide manner in late stages of the male germline and identify underlying mechanisms. SCML2, a germline-specific subunit of a Polycomb repressive complex 1 (PRC1), establishes the unique epigenome of the male germline through two distinct antithetical mechanisms. SCML2 works with PRC1 and promotes RNF2-dependent ubiquitination of H2A, thereby marking somatic/progenitor genes on autosomes for repression. Paradoxically, SCML2 also prevents RNF2-dependent ubiquitination of H2A on sex chromosomes during meiosis, thereby enabling unique epigenetic programming of sex chromosomes for male reproduction. Our results reveal divergent mechanisms involving a shared regulator by which the male germline epigenome is distinguished from that of the soma and progenitor cells. RNA-seq and ChIP-seq analyses using wild-type and Scml2 KO spermatogenic cells.配子发生依赖于生殖系特异性基因的表达。然而，生殖系表观基因组如何区别于体细胞谱系并完成特异性建立，这一问题仍未阐明。本研究发现，在雄性生殖系的晚期阶段，通常在体细胞谱系与精子发生祖细胞中表达的基因会经历全基因组范围的沉默，并揭示了其背后的分子机制。SCML2作为多梳抑制复合体1（Polycomb repressive complex 1，PRC1）的生殖系特异性亚基，通过两种截然不同的对立机制构建雄性生殖系独特的表观基因组：SCML2与PRC1协同作用，促进RNF2依赖的组蛋白H2A泛素化修饰，进而标记常染色体上的体细胞/祖细胞基因以实现沉默；矛盾的是，SCML2在减数分裂过程中还会抑制性染色体上RNF2依赖的H2A泛素化修饰，从而使性染色体能够完成适配雄性生殖的独特表观遗传编程。本研究结果揭示了一种共享调控因子介导的差异化机制，借此雄性生殖系表观基因组得以区别于体细胞与祖细胞的表观基因组。本研究使用野生型与Scml2基因敲除（KO）的生精细胞开展了RNA测序（RNA-seq）与染色质免疫共沉淀测序（ChIP-seq）分析。