RNF8 and SCML2 cooperate to regulate ubiquitination and H3K27 acetylation for escape gene activation on the sex chromosomes.
RNF8 and SCML2 cooperate to regulate ubiquitination and H3K27 acetylation for escape gene activation on the sex chromosomes.
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DOI：
10.1371/journal.pgen.1007233
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发表时间：
2018-03
期刊：
影响因子：
4.5
通讯作者：
Namekawa SH
中科院分区：
文献类型：
--
作者：
Adams SR;Maezawa S;Alavattam KG;Abe H;Sakashita A;Shroder M;Broering TJ;Sroga Rios J;Thomas MA;Lin X;Price CM;Barski A;Andreassen PR;Namekawa SH
性染色体富含在精子发生的晚期阶段被激活的生殖系基因。由于减数分裂性染色体失活（MSCI），这些性染色体连锁基因必须逃脱沉默激活精子细胞，从而确保其功能的男性生殖。RNF8是一种DNA损伤反应蛋白，SCML2是一种生殖细胞特异性多梳蛋白，是该过程的两种主要的已知调节剂。在这里，我们表明RNF8和SCML2合作，以调节减数分裂过程中的泛素化，早期步骤，建立积极的组蛋白修饰，随后的基因激活。Rnf8和Scml2的双突变体揭示了组蛋白H2A在赖氨酸119（H2AK119ub）处的RNF8依赖性单泛素化被SCML2去泛素化，证明了RNF8和SCML2在泛素调节中的相互作用。此外，我们确定了RNF8和SCML2在泛素化调节中的不同功能：SCML2使RNF8非依赖性H2AK119ub去泛素化，但不使RNF8依赖性多聚泛素化去泛素化。RNF8依赖性多泛素化是建立H3K27乙酰化所必需的，H3K27乙酰化是活性增强子的标志物，而持久性H2AK119ub抑制H3K27乙酰化的建立。在H3K27乙酰化的沉积之后，H3K4二甲基化被确立为准备启动子上的活性标记。总之，我们提出了一个模型，其中泛素的调节导致组织平衡的增强子和启动子在减数分裂，诱导随后的基因激活，否则沉默的性染色体在减数分裂后精子细胞。为了产生未受损的精子，精确激活生殖细胞特异性基因是精子发生后期的重要步骤。然而，携带这些基因的性染色体在减数分裂期间以染色体范围的方式沉默，这一过程称为减数分裂性染色体失活。性染色体失活从减数分裂到减数分裂后的精子细胞一直维持。因此，为了确保男性生殖所需的性染色体连锁（性连锁）基因的功能，这些基因必须在精子细胞中逃避沉默而激活。在这里，我们揭开了表观遗传机制，激活性连锁基因，否则在男性生殖细胞的非活性性染色体的基础。我们确定了两个因素调节基因激活的机制：一个是RNF8，一种DNA损伤反应蛋白，另一个是SCML2，一种种系特异性Polycomb蛋白。我们的数据表明，在减数分裂过程中，RNF8和SCML2合作，以调节泛素化，建立积极的表观遗传修饰的增强子和启动子，随后的基因激活，这些记忆是通过减数分裂维持，以诱导精子细胞中的基因激活。重要的是，这项研究揭示了精子细胞中特定基因激活的新的表观遗传机制，并阐明了男性不育的潜在原因。
The sex chromosomes are enriched with germline genes that are activated during the late stages of spermatogenesis. Due to meiotic sex chromosome inactivation (MSCI), these sex chromosome-linked genes must escape silencing for activation in spermatids, thereby ensuring their functions for male reproduction. RNF8, a DNA damage response protein, and SCML2, a germline-specific Polycomb protein, are two major, known regulators of this process. Here, we show that RNF8 and SCML2 cooperate to regulate ubiquitination during meiosis, an early step to establish active histone modifications for subsequent gene activation. Double mutants of Rnf8 and Scml2 revealed that RNF8-dependent monoubiquitination of histone H2A at Lysine 119 (H2AK119ub) is deubiquitinated by SCML2, demonstrating interplay between RNF8 and SCML2 in ubiquitin regulation. Additionally, we identify distinct functions of RNF8 and SCML2 in the regulation of ubiquitination: SCML2 deubiquitinates RNF8-independent H2AK119ub but does not deubiquitinate RNF8-dependent polyubiquitination. RNF8-dependent polyubiquitination is required for the establishment of H3K27 acetylation, a marker of active enhancers, while persistent H2AK119ub inhibits establishment of H3K27 acetylation. Following the deposition of H3K27 acetylation, H3K4 dimethylation is established as an active mark on poised promoters. Together, we propose a model whereby regulation of ubiquitin leads to the organization of poised enhancers and promoters during meiosis, which induce subsequent gene activation from the otherwise silent sex chromosomes in postmeiotic spermatids. To produce unimpaired sperm, precise activation of germline-specific genes is an essential step during the late stages of spermatogenesis. However, sex chromosomes carrying these genes become silenced in a chromosome-wide manner during meiosis in a process called meiotic sex chromosome inactivation. Sex chromosome inactivation is maintained from meiosis into postmeiotic spermatids. Thus, to ensure the function of sex chromosome-linked (sex-linked) genes required for male reproduction, these genes must escape silencing for activation in spermatids. Here, we unravel the epigenetic mechanisms that underlie the activation of sex-linked genes from otherwise inactive sex chromosomes in the male germline. We determine the mechanism by which two factors regulate gene activation: one is RNF8, a DNA damage response protein, and the other is SCML2, a germline-specific Polycomb protein. Our data suggest that, during meiosis, RNF8 and SCML2 cooperate to regulate ubiquitination, which establishes active epigenetic modifications on enhancers and promoters for subsequent gene activation; these memories are maintained through meiotic divisions to induce gene activation in spermatids. Importantly, this study uncovers novel epigenetic mechanisms that underlie specific gene activation in spermatids and illuminates potential causes of male infertility.
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