Epigenetic Regulation of Gene Expression during Spermatogenesis

摘要 这项研究的目标是阐明全基因组动态背后的表观遗传学机制。 精子发生过程中的基因表达。生殖细胞的基因表达程序不同于 体细胞的血统。重要的是，体细胞基因表达程序在很大程度上在雄性生殖细胞中被抑制 细胞。相反，男性生殖细胞保留了一种独特的细胞身份，这种身份传递给精子，并产生一种 受精后的全能受精卵。我们最近的rna-seq分析显示，大约有3000 精子发生特异的基因被激活，而大约3000个基因在两者中表达 雄性生殖系的体细胞谱系和祖细胞(称为体细胞/祖细胞基因)主要是 在精子发生后期，即在减数分裂和减数分裂后的精子细胞中被抑制。我们鉴定出SCML2 作为体细胞/祖细胞基因的抑制者。SCML2是Polcomb的种系特异性亚基 抑制复合体1(PRC1)，发育过程中可遗传基因抑制的调节因子。我们有 发现多梳复合体通过对两者的基因编程来决定基因表达谱 压抑和激活。我们的综合结果表明，未分化精原细胞的表观基因组 是为随后的全基因组基因沉默和激活而预置的(称为预编程的 精子发生(称为“程序性分化”)。目前尚不清楚的是， 多梳蛋白在精子发生过程中调节基因表达。我们的中心假设是 在未分化的精原细胞中，多梳蛋白相互协作预先编程表观基因组，因此 调节随后的动态全基因组表达谱和程序性分化 精子发生所必需的。这项研究将解决未分化的表观基因组如何 精原细胞准备对分化信号做出反应，然后，分化程序如何 是通过有丝分裂和减数分裂来维持的。我们设计了两个相辅相成的具体目标。在……里面 目的1，我们将阐明Prc1如何定义精子发生过程中可遗传基因的激活和沉默。在……里面 目的2，我们将讨论SCML2如何为以后的生精分化预先编程表观基因组。这些 研究将揭示新的表观遗传机制，通过这种机制，多梳蛋白之间的相互作用调节 精子发生过程中基因的动态表达。

ABSTRACT The goal of this study is to elucidate the epigenetic mechanisms underlying dynamic genome-wide gene expression during spermatogenesis. The gene expression program of germ cells is distinct from that of somatic lineages. Importantly, the somatic gene expression program is largely suppressed in male germ cells. Instead, male germ cells retain a unique cellular identity that is passed on to sperm and gives rise to a totipotent zygote after fertilization. Our recent RNA-seq analysis showed that about three thousand spermatogenesis-specific genes are activated, while approximately three thousand genes expressed in both somatic lineages and progenitor cells of the male germline (termed somatic/progenitor genes) are largely suppressed during late spermatogenesis, i.e., in meiosis and in postmeiotic spermatids. We identified SCML2 as the suppressor of somatic/progenitor genes. SCML2 is a germline-specific subunit of the Polycomb repressive complex 1 (PRC1), a regulator of heritable gene repression during development. We have discovered that Polycomb complexes determine the gene expression profile by programming genes for both repression and activation. Our combined results suggest that the epigenome of undifferentiated spermatogonia is preset (termed “preprogrammed”) both for subsequent genome-wide gene silencing and activation during spermatogenesis (termed “programmed differentiation”). What remain unknown are the mechanisms whereby Polycomb proteins regulate gene expression during spermatogenesis. Our central hypothesis is that Polycomb proteins cooperate to preprogram the epigenome in undifferentiated spermatogonia, thus regulating the subsequent dynamic genome-wide expression profile and programmed differentiation necessary for spermatogenesis. This study will address how the epigenome of undifferentiated spermatogonia is prepared to respond to differentiation cues and, afterwards, how the differentiation program is maintained through mitotic and meiotic divisions. We have designed two complementary specific aims. In Aim 1, we will elucidate how PRC1 defines heritable gene activation and silencing during spermatogenesis. In Aim 2, we will address how SCML2 preprograms the epigenome for later spermatogenic differentiation. These studies will reveal novel epigenetic mechanisms by which interplay between Polycomb proteins regulates the dynamic gene expression during spermatogenesis.