Histone Demethylase Control of Post Implantation Development

摘要 当细胞命运由特定基因决定时，多细胞生物的功能特化就产生了 表达模式与转录因子一起工作的表观遗传修饰使细胞身份成为可能。早期 在发育过程中，少数细胞在上胚层阶段迁移到性腺成为原始生殖细胞（PGCs）， 它们是配子的前体PGCs经历一系列有序的整体表观遗传变化， 减少了抑制性修饰：H3赖氨酸9甲基化（H3 K9 me 2）和DNA甲基化， 抑制重复元件的表达以维持基因组的完整性，并被其他标记所取代， 如H2 A/H4精氨酸甲基化（H2 A/H4 R3 me 2）。这些表观遗传的精确时间调节 这些事件是协调的，它们的相互依存关系仍然不为人所知。错误或部分擦除. 特定的位置可能会导致印记缺陷以及无意中的跨代遗传。我们 已经发现H3 K9 me 2脱甲基酶KDM 3B通过泰特酶控制DNA脱甲基化 并与PRMT 5（H2 A/H4 R3甲基转移酶）相互作用。尽管H3 K9 me 2是一种抑制性组蛋白， 通过修饰，我们发现KDM 3B和KDM 3A与mRNA加工机制相互作用。采取 我们共同假设KDM 3家族的蛋白质协调着床后发育为PGC 通过表观遗传和转录后机制，这将在本提案中进行研究。

ABSTRACT Functional specialization in a multicellular organism arises when cell fate is established by a specific gene expression pattern. Epigenetic modifications working with transcription factors enable cell identity. During early development a few cells migrate at the epiblast stage to the gonad to become Primordial germ cells (PGCs), which are the precursors of gametes. PGCs undergo an ordered series of global epigenetic changes that decimates the repressive modifications: H3 lysine 9 methylation (H3K9me2) and DNA methylation, which suppress expression of repetitive elements to maintain genomic integrity, and is replaced by other marks such as H2A/H4 arginine methylation (H2A/H4R3me2). How the precise temporal regulation of these epigenetic events is coordinated and their interdependence remains poorly understood. Incorrect or partial erasure at specific locations could lead to imprinting defects as well as inadvertent transgenerational inheritance. We have discovered that the H3K9me2 demethylase, KDM3B, controls DNA demethylation by the Tet enzymes and interacts with PRMT5, a H2A/H4R3 methyltransferase. Despite H3K9me2 being a repressive histone modification, we have found that KDM3B and KDM3A interact with mRNA processing machinery. Taken together we hypothesize that proteins of the KDM3 family orchestrate post-implantation development to PGCs by epigenetic and post-transcriptional mechanisms, which will be investigated in this proposal.