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: 10292862
• 负责人: Satoshi Namekawa
• 金额: $ 31.4万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 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/10292862
• 关键词: Address; Applications Grants; Catalytic Domain; Cell Differentiation process; ChIP-seq; Child; Clinical; Complex; Couples; Cues; Defect; Development; Ensure; Epigenetic Process; 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; Spermatocytes; Spermatogenesis; Spermatogonia; 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; stem cells; transcription factor; transcriptome sequencing; zygote; Address; Applications Grants; Catalytic Domain; Cell Differentiation process; ChIP-seq; Child; Clinical; Complex; Couples; Cues; Defect; Development; Ensure; Epigenetic Process; 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; Spermatocytes; Spermatogenesis; Spermatogonia; 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; stem cells; 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.

抽象的 这项研究的目的是阐明范围内动态基因组的表观遗传机制 精子发生过程中的基因表达。生殖细胞的基因表达程序与 躯体谱系。重要的是，在男性细菌中，体细胞基因表达程序在很大程度上受到抑制 细胞。相反，雄性生殖细胞保留了独特的细胞身份，该身份传递给了精子，并产生 受精后的全能合子。我们最近的RNA-seq分析表明，大约三千 精子发生特异性基因被激活，而大约三千个基因在两者中表达 男性种系的体细胞和祖细胞（称为体细胞/祖细胞基因）在很大程度上是 在精子发生晚期，即减数分裂和症状后精子中被抑制。我们确定了SCML2 作为体细胞/祖细胞基因的抑制剂。 SCML2是polycomb的种系特异性亚基 抑制性复合物1（PRC1），在发育过程中可遗传基因表达的调节剂。我们有 发现通过编程基因来确定基因表达谱 抑制和激活。我们的综合结果表明，未分化精子的表观组 在随后的全基因组基因沉默和激活过程中，都是预设（称为“预编程”） 精子发生（称为“编程分化”）。仍然未知的是机制 聚酮蛋白调节精子发生过程中的基因表达。我们的中心假设是 Polycomb蛋白协调以预编程未分化的精子中的表观基因组，因此 调节随后的动态全基因组表达谱和编程分化 精子发生所必需的。这项研究将解决未分化的表观组 精子症准备对差异提示做出反应，之后，分化计划如何 通过有丝分裂和减数分裂划分维护。我们设计了两个完整的特定目标。在 AIM 1，我们将阐明PRC1在精子发生过程中如何定义可遗传的基因激活和沉默。 AIM 2，我们将解决SCML2如何对表观基因组进行预编程以进行以后的精子分化。这些 研究将揭示新型的表观遗传机制，通过这些机制，多肉蛋白之间的相互作用调节 精子发生过程中的动态基因表达。