Histone Demethylase Control of Post Implantation Development

组蛋白去甲基化酶对植入后发育的控制

基本信息

批准号：
10596098
负责人：
Rupa Sridharan
金额：
$ 38.94万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10596098
关键词：
Adenosine Affect Arginine Cell Nucleus Cells Chromatin Cues Cytosine DNA DNA Methylation Data Defect Dependence Development Elements Enabling Factors Environment Enzymes Epiblast Epigenetic Process Event Excision Family Fertilization Gene Expression Gene Expression Profile Gene Silencing Genes Genetic Genome Germ Cells Gonadal structure Histones Immunofluorescence Immunologic Infertility Location Lysine Measures Mediating Messenger RNA Methods Methylation Methyltransferase Modification Mus Nuclear Translocation Organism Pattern Phenotype Play Post-Transcriptional Regulation Proteins RNA RNA Splicing Repetitive Sequence Reporting Repression Role Series Signal Transduction Specific qualifier value Structure of primordial sex cell Testing Tetanus Helper Peptide Tissues Totipotent active control arginine methyltransferase cell motility chromatin immunoprecipitation demethylation design developmental disease embryonic stem cell epigenetic regulation epitranscriptome epitranscriptomics genome integrity genome-wide genomic locus histone demethylase histone modification implantation imprint in vitro Model in vivo insight migration non-genetic posttranscriptional prevent protein complex recruit transcription factor transcriptome transgenerational epigenetic inheritance transmission process zygote

项目摘要

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.

抽象的当细胞命运由特定基因确定时，多细胞生物体中的功能专门化就会出现表达模式。表观遗传修饰与转录因子一起作用可实现细胞身份。早期期间发育过程中，一些细胞在外胚层阶段迁移到性腺，成为原始生殖细胞（PGC），它们是配子的前身。 PGC 经历一系列有序的全局表观遗传变化，消除抑制性修饰：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维持基因组完整性，并被其他标记所取代，例如作为 H2A/H4 精氨酸甲基化 (H2A/H4R3me2)。这些表观遗传的精确时间调控如何事件是协调一致的，但它们的相互依赖性仍然知之甚少。错误或部分擦除特定位置可能导致印记缺陷以及无意的跨代遗传。我们发现 H3K9me2 去甲基化酶 KDM3B 通过 Tet 酶控制 DNA 去甲基化并与 PRMT5（一种 H2A/H4R3 甲基转移酶）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。采取我们共同假设 KDM3 家族的蛋白质协调 PGC 的植入后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。