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

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

项目成果

Isolation of Murine Spermatogenic Cells using a Violet-Excited Cell-Permeable DNA Binding Dye.

使用紫罗兰色的细胞渗透DNA结合染料分离鼠精子生成细胞。

• DOI: 10.3791/61666
• 发表时间: 2021-01-14
• 期刊: Journal of visualized experiments : JoVE
• 作者: Yeh YH;Hu M;Nakagawa T;Sakashita A;Yoshida S;Maezawa S;Namekawa SH
• 通讯作者: Namekawa SH

Super-enhancer switching drives a burst in gene expression at the mitosis-to-meiosis transition.

• DOI: 10.1038/s41594-020-0488-3
• 发表时间: 2020-10
• 期刊: Nature structural & molecular biology
• 影响因子: 16.8
• 作者: Maezawa S;Sakashita A;Yukawa M;Chen X;Takahashi K;Alavattam KG;Nakata I;Weirauch MT;Barski A;Namekawa SH
• 通讯作者: Namekawa SH

Endogenous retroviruses drive species-specific germline transcriptomes in mammals.

• DOI: 10.1038/s41594-020-0487-4
• 发表时间: 2020-10
• 期刊: Nature structural & molecular biology
• 影响因子: 16.8
• 作者: Sakashita A;Maezawa S;Takahashi K;Alavattam KG;Yukawa M;Hu YC;Kojima S;Parrish NF;Barski A;Pavlicev M;Namekawa SH
• 通讯作者: Namekawa SH

A rapidly evolved domain, the SCML2 DNA-binding repeats, contributes to chromatin binding of mouse SCML2†.

SCML2 DNA 结合重复序列是一个快速进化的结构域，有助于小鼠 SCML2 的染色质结合。

• DOI: 10.1093/biolre/ioy181
• 发表时间: 2019
• 期刊: Biology of reproduction
• 影响因子: 3.6
• 作者: Maezawa,So;Alavattam,KrisG;Tatara,Mayu;Nagai,Rika;Barski,Artem;Namekawa,SatoshiH
• 通讯作者: Namekawa,SatoshiH