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：
10367127
负责人：
Rupa Sridharan
金额：
$ 39.61万
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/10367127
关键词：
Adenosine Affect Arginine Cell Nucleus Cells Chromatin Cues Cytosine DNA DNA Methylation Data Defect Dependence Development Elements Environment Enzymes Epiblast Epigenetic Process Event Excision Family Fertilization Gene Expression Gene Expression Profile Gene Silencing Genes Genetic Genetic Transcription Genome Germ Cells Gonadal structure Histones Immunofluorescence Immunologic Infertility Lead Location Lysine Measures Mediating Messenger RNA Methods Methylation Methyltransferase Modification Mus Nuclear Translocation Organism Pattern Phenotype Play Post-Transcriptional Regulation Protein Analysis Proteins RNA RNA Splicing Repetitive Sequence Reporting Role Series Signal Transduction Specific qualifier value Structure of primordial sex cell Testing Tetanus Helper Peptide Tissues Totipotent active control arginine methyltransferase 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 non-genetic 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.

抽象的当特定基因建立细胞命运时，在多细胞生物中的功能专业化会产生表达模式。与转录因子一起使用的表观遗传修饰使细胞身份。在早期开发几个细胞在epiblast阶段迁移到性腺，成为原始生殖细胞（PGC），这是配子的前体。 PGC经历了一系列有序的全球表观遗传变化，破坏抑制性修饰：H3赖氨酸9甲基化（H3K9ME2）和DNA甲基化，它们抑制重复元素的表达以维持基因组完整性，并被其他标记所取代作为H2A/H4精氨酸甲基化（H2A/H4R3ME2）。这些表观遗传学的精确时间调节如何事件是协调的，它们的相互依存关系仍然很少理解。不正确或部分擦除特定的位置可能导致烙印缺陷以及无意转换遗传。我们已经发现H3K9ME2脱甲基酶KDM3B控制TET酶DNA脱甲基化并与H2A/H4R3甲基转移酶的PRMT5相互作用。尽管H3K9ME2是一个抑制性组蛋白修改后，我们发现KDM3B和KDM3A与mRNA处理机械相互作用。拍摄我们共同假设KDM3家族的蛋白质编排了植入后发展到PGCS 通过表观遗传和转录后机制，将在此提案中进行研究。