Control of early germline development in C. elegans

项目总结/摘要 我的研究计划的长期目标是了解表观遗传信息是如何传递的 在几代人和发展过程中。表观遗传机制使基因表达和 发育不仅受DNA序列的调控，还受DNA包装到染色质中的方式的调控。 通过染色质包装或“表观基因组”忠实地传递信息的机制， DNA复制到子细胞和从父母到后代仍然是个谜。我的实验室开发了一种 研究这些机制的强大模型。在秀丽隐杆线虫中， 组蛋白修饰酶使胚胎遗传的亲本染色体能够传递一种 从亲代生殖细胞到子代原始生殖细胞的表观遗传“生殖系记忆”。 没有继承这种记忆的生殖细胞就会死亡。关键的参与者是MES-4， 具有ON标记的基因组区域（组蛋白H3在Lys 36或H3 K36 me上的甲基化），以及Polycomb 抑制复合物2或PRC 2，用OFF标记标记基因组的抑制区域 （H3K27me）。我们的工作假设是1）MES-4和PRC 2将基因组区域标记为转录 (ON)2）这种ON和OFF标记的模式被传递到 后代通过卵母细胞和精子染色质，和3）母体提供的MES-4和PRC 2繁殖的 通过细胞分裂的模式，为生殖细胞提供适当的基因表达“蓝图”， 发展我们的目标是测试这一假设的关键方面。在目标1中，我们将确定精子和 每个卵母细胞表观基因组将“生殖系记忆”传递给后代。我们将阐明 精子和卵母细胞基因组上的关键组蛋白标记，特定精子和卵母细胞标记的命运 早期胚胎细胞的模式，以及精子或卵母细胞标记改变对生殖系的影响 在后代的发展。在目标2中，我们将确定标记和未标记的染色质状态如何 通过靶向MES-4和PRC 2作用通过细胞分裂忠实地繁殖。在目标3中，我们将测试 亲本中的MES-4和PRC 2标记调节PGCs中的转录程序，并且如果改变 通过将亲本蠕虫暴露于环境应激，在亲本种系中的转录导致改变的 染色体标记和转录模式。 对人群的流行病学研究表明，父母的经历会影响他们的生活。 生理、健康和寿命的影响。生殖细胞是 两代人之间。我们的研究是跨代表观遗传的核心， 提供生殖细胞生物学的重要见解，染色质状态如何从父母传递信息， 研究的重点是如何对后代的健康和寿命产生影响，以及父母的经历如何影响后代的健康和寿命。

Project Summary/Abstract The long-term objective of my research program is to understand how epigenetic information is transmitted across generations and during development. Epigenetic mechanisms enable gene expression and development to be regulated not only by DNA sequence but also by how DNA is packaged into chromatin. The mechanisms for faithfully transmitting information via chromatin packaging or the “epigenome” through DNA replication to daughter cells and from parents to offspring remain mysterious. My lab has developed a powerful model for investigating those mechanisms. In the nematode Caenorhabditis elegans, a set of histone-modifying enzymes enables the parental chromosomes inherited by embryos to transmit an epigenetic “memory of germline” from parent germ cells to the primordial germ cells (PGCs) in offspring. Germ cells that do not inherit that memory die. The key players are MES-4, which marks transcribed regions of the genome with an ON mark (methylation of histone H3 on Lys 36 or H3K36me), and Polycomb Repressive Complex 2 or PRC2, which marks repressed regions of the genome with an OFF mark (H3K27me). Our working hypothesis is that 1) MES-4 and PRC2 mark genomic regions as transcribed (ON) or repressed (OFF) in the parental germline, 2) that pattern of ON and OFF marking is passed to offspring via oocyte and sperm chromatin, and 3) maternally provided MES-4 and PRC2 propagate the pattern through cell divisions to provide the PGCs with proper gene expression “blueprints” for germline development. Our aims test key aspects of this hypothesis. In Aim 1, we will determine if the sperm and oocyte epigenomes each transmit a “memory of germline” to offspring. We will elucidate the distributions of critical histone marks on the sperm and oocyte genomes, the fates of specific sperm and oocyte marking patterns in early embryonic cells, and the consequences of altered sperm or oocyte marking to germline development in offspring. In Aim 2, we will determine how marked and unmarked chromatin states are faithfully propagated through cell divisions by targeted MES-4 and PRC2 action. In Aim 3, we will test if MES-4 and PRC2 marking in parents regulates the transcription program in PGCs, and if altering transcription in the parental germline, by exposing parent worms to environment stresses, leads to altered chromatin marking and transcription patterns in offspring. Epidemiological studies of human populations suggest that what parents experience can affect the physiology, health, and lifespan of their offspring and even grand-offspring. The germline is the conduit between generations. Our studies, which lie at the heart of transgenerational epigenetic inheritance, will provide critical insights into germ cell biology, how chromatin states transmit information from parents to offspring, and how parental experiences may influence the health and longevity of future generations.