Epigenetic control of spermatogonial stem cell self-renewal

精原干细胞自我更新的表观遗传控制

基本信息

批准号：
10656855
负责人：
Peijing Jeremy Wang
金额：
$ 40.68万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-05 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10656855
关键词：
ATAC-seq Adult Animals Biological Biological Assay Cells ChIP-seq Chemicals Chromatin Chromatin Remodeling Factor Data Dissection Donor person Epigenetic Process Equilibrium Etiology Failure Foundations Gene Cluster Gene Expression Gene Transfer Techniques Generations Genes Genetic Genetic Transcription Genetic study Genome Genomics Germ Cells Histone H3 Homeobox Genes Immunoprecipitation In Vitro Infertility Informal Social Control Intrinsic factor Life Male Infertility Mass Spectrum Analysis Mediating Methylation Methyltransferase Molecular Mus Nucleosomes Play Production Proteins Proteomics RNA Polymerase II Regulation Reproductive Medicine Research Resolution Role Small Interfering RNA Spermatogenesis Spermatogonia Stem cell transplant Testis Transcriptional Activation Transplantation ZNF145 gene cancer cell cytokine glial cell-line derived neurotrophic factor inhibitor innovation insight knock-down male male fertility multiple omics mutant novel progenitor programs recruit self-renewal single-cell RNA sequencing sperm cell stem cell biology stem cell division stem cell niche stem cell population stem cell self renewal stem cells transcription factor transcriptome sequencing translational applications

项目摘要

Project Summary Males produce sperm continuously through adult life, driven by the renewal of spermatogonial stem cells (SSCs). The long-term objective of this application is to determine the role of a novel epigenetic program that we have recently identified in regulating the renewal of adult SSCs. SSCs can both self-renew and produce progenitor spermatogonia that will differentiate to initiate spermatogenesis. The balance between SSC self- renewal and differentiation is key for life-long production of sperm in adult males. Both SSC transplantation and in vitro SSC cultures have enabled functional studies of SSC and allowed for advancement of translational applications in animal transgenesis. However, while much is known about spermatogenesis, the regulation of SSC self-renewal remains poorly understood. Stem cell renewal requires both stem cell-intrinsic factors and external niche factors, only a handful of which have been identified (PLZF, RB, NANOS2, GDNF, ETV5, etc.). Notably, their functions in SSC self-renewal have been revealed through genetic studies. Despite these advances, the molecular biological control of SSC remains poorly understood. We have identified an epigenetic factor DOT1L, the sole H3K79 methyltransferase, as a novel master regulator of mouse SSC self- renewal. Moreover, by chemically inhibiting DOT1L, we were able to identify specific target genes that likely contribute to SSC renewal. We propose an innovative multi-pronged (genetic, chemical, genomic, and proteomic) approach to comprehensively elucidate this novel epigenetic program in SSCs. As failure in SSC self-renewal leads to a lack of sperm production and thus male infertility, completion of this project will lay a firm foundation for molecular dissection of SSC stem cell renewal and open new avenues of research in SSC biology and reproductive medicine.

项目概要在精原干细胞更新的驱动下，男性在成年后持续产生精子（SSC）。该应用的长期目标是确定新型表观遗传程序的作用，该程序我们最近确定了对成人 SSC 更新的监管。 SSC既可以自我更新，又可以产生祖精原细胞将分化以启动精子发生。 SSC自我之间的平衡更新和分化是成年男性终生产生精子的关键。 SSC移植和体外 SSC 培养物使 SSC 的功能研究成为可能，并促进了转化研究的进展在动物转基因中的应用然而，尽管人们对精子发生了解很多，但 SSC 的自我更新仍然知之甚少。干细胞更新需要干细胞内在因素和外部利基因素，其中只有少数已被识别（PLZF、RB、NANOS2、GDNF、ETV5 等）。值得注意的是，它们在 SSC 自我更新中的功能已通过遗传学研究揭示。尽管有这些尽管取得了进展，但 SSC 的分子生物学控制仍然知之甚少。我们已经确定了一个表观遗传因子 DOT1L（唯一的 H3K79 甲基转移酶）作为小鼠 SSC 自身的新型主调节因子更新。此外，通过化学抑制 DOT1L，我们能够识别可能的特定靶基因为SSC更新做出贡献。我们提出了一种创新的多管齐下（遗传、化学、基因组和蛋白质组学）方法全面阐明 SSC 中的这种新颖的表观遗传程序。由于 SSC 失败自我更新导致精子生成不足，从而导致男性不育，该项目的完成将为为 SSC 干细胞更新的分子解剖奠定坚实的基础，并开辟 SSC 研究的新途径生物学和生殖医学。