Epigenetic Regulation of Gene Expression during Spermatogenesis

精子发生过程中基因表达的表观遗传调控

• 批准号: 9894901
• 负责人: Satoshi Namekawa
• 金额: $ 17.72万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-15 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894901
• 关键词: Address; Applications Grants; Catalytic Domain; Cell Differentiation process; ChIP-seq; Child; Clinical; Complex; Couples; Cues; Defect; Development; Ensure; Epigenetic Process; Expression Profiling; Fertilization; Foundations; Gene Activation; Gene Chips; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Silencing; Genes; Genomics; Germ Cells; Goals; Heritability; Infertility; Knockout Mice; Knowledge; Link; Male Infertility; Malignant neoplasm of testis; Mediating; Meiosis; Memory; Mitotic; Modeling; Outcome Study; PRC1 Protein; Polycomb; Proteins; Public Health; Regulation; Repression; Reproductive Medicine; Research; Role; Spermatids; Spermatogenesis; Spermatogonia; Stem cells; Totipotency; Totipotent; Translating; Undifferentiated; autosome; base; design; embryonic stem cell; epigenetic memory; epigenetic regulation; epigenome; epigenomics; expectation; gene repression; genetic analysis; genome-wide; loss of function; male; male fertility; mouse model; mutant; novel; progenitor; programs; protein function; recruit; sperm cell; transcription factor; transcriptome sequencing; zygote

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.

摘要 本研究的目的是阐明动态基因组范围内的表观遗传机制 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 身体谱系。重要的是，体细胞基因表达程序在很大程度上抑制在男性生殖 细胞相反，男性生殖细胞保留了一种独特的细胞身份，这种身份被传递给精子，并产生一种 受精后的全能合子。我们最近的RNA-seq分析显示， 精子发生特异性基因被激活，而大约三千个基因在两个细胞中表达。 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 在精子发生后期受到抑制，即，在减数分裂和减数分裂后精子细胞中。我们发现了SCML 2 作为体细胞/祖细胞基因的抑制基因。SCML 2是Polycomb基因的一个种系特异性亚基， 抑制复合物1（PRC 1），发育过程中可遗传基因抑制的调节因子。我们有 发现Polycomb复合物通过对基因进行编程来决定基因表达谱， 抑制和激活。我们的综合结果表明，未分化精原细胞的表观基因组 是预设的（称为“预编程的”），用于随后的全基因组基因沉默和激活， 精子发生（称为“程序化分化”）。目前尚不清楚的是 多梳蛋白调控精子发生过程中的基因表达。我们的核心假设是， 多梳蛋白协同对未分化精原细胞的表观基因组进行预编程， 调节随后的动态全基因组表达谱和程序化分化 是精子生成所必需的本研究将探讨表观基因组如何在未分化的 精原细胞准备好对分化线索做出反应，然后，分化程序如何 是通过有丝分裂和减数分裂来维持的。我们设计了两个互补的具体目标。在 目的1，我们将阐明PRC 1如何定义在精子发生过程中遗传基因的激活和沉默。在 目的2，我们将讨论SCML 2如何预编程表观基因组为以后的精子发生分化。这些 研究将揭示新的表观遗传机制，通过这种机制，Polycomb蛋白之间的相互作用调节了 精子发生过程中基因的动态表达。