Histone Demethylase Control of Post Implantation Development

摘要 当细胞命运由特定的基因决定时，多细胞生物体的功能特化就出现了。 表达模式。与转录因子一起工作的表观遗传修饰使细胞具有同一性。在早期 发育：少数细胞在上胚期向性腺迁移，成为原始生殖细胞(PGCs)， 它们是配子的前身。PGC经历了一系列有序的全球表观遗传变化 摧毁抑制修饰：H3赖氨酸9甲基化(H3K9me2)和DNA甲基化，这 抑制重复元件的表达以保持基因组的完整性，并被其他标记取代，如 H_2A/H_4精氨酸甲基化(H_2A/H_4R3me2)。这些表观遗传学的精确时间调控 这些事件是相互协调的，它们之间的相互依存关系仍然鲜为人知。不正确或部分擦除 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 发现H3K9me2去甲基酶KDM3B控制Tet酶的DNA去甲基化 并与H_2A/H_4R3甲基转移酶PRMT5相互作用。尽管H3K9me2是一种抑制性组蛋白 修饰后，我们发现KDM3B和KDM3A与mRNA加工机制相互作用。已被占用 我们共同假设KDM3家族的蛋白质协调着床后对原生殖细胞的发育 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.