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Investigating the epigenetic mechanisms surrounding neuronal stem cell differentiation

研究神经元干细胞分化的表观遗传机制

基本信息

批准号：
10424864
负责人：
David Alexander Vinson
金额：
$ 2.25万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2022-04-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10424864
关键词：
Acetylation Binding Brain Bromodeoxyuridine Caenorhabditis elegans Cell Lineage Cell Maintenance Cells ChIP-seq Chromatin Complex DNA DNA Damage Data Detection Development Disease Environment Enzymatic Biochemistry Enzymes Epigenetic Process Eukaryota Family Genes Genetic Transcription Genome Genomics Goals Histone Code Histone H3 Histones In Vitro Knock-out Light Location Lysine Maintenance Mass Spectrum Analysis Meiosis Methylation Molecular Morphology Mus Mutation Neurodevelopmental Disorder Neuronal Differentiation Neurons Nucleosomes Organism Pathway interactions Pattern Pharmacology Phenotype Play Ploidies Positioning Attribute Post-Translational Protein Processing Proteins Publishing Reader Repetitive Sequence Rodent Role Site Spermatogenesis Symptoms Time Tissues Work base brain tissue chromatin remodeling combinatorial demethylation differential expression epigenome genome integrity mutant nerve stem cell neurogenesis neuron development novel preservation protein complex recruit relating to nervous system response sperm cell stem cell differentiation stem cells

项目摘要

Project Summary/Abstract Chromatin, formed from highly regulated interactions of DNA with the histone proteins (H2A, H2B, H3 and H4), helps eukaryotes regulate genome integrity, transcriptional, and epigenetic pathways. Histone proteins can be post-translationally modified (PTM) at select residues, which include lysine methylation and acetylation. These histone PTMs recruit protein complexes that further modulate the activity of the nearby chromatin environment (Jenuwein and Allis et. al., 2001). However, the mechanistic details of how histone PTMs modify enzymatic activities on chromatin remain poorly understood. Previously, our lab discovered a novel histone PTM on histone H3, H3K23me3, which protects highly repetitive regions of the genome during meiosis in T. thermophila and C. elegans (Papazyan et. al., 2014). Recently we showed that a lysine demethylase, KDM4B, selectively associates with H3K23me3 in differentiating mammalian sperm and that the H3K23me3-KDM4B interaction leads to demethylation of H3K36me3, in vitro (Su et. al., 2016). A combination of published work (Fujiwara et. al., 2016) and unpublished data from our lab show that both H3K23me3 and KDM4B are also highly enriched in newly differentiated mammalian neurons in brain tissue and in cultured neurons. Interestingly, this published work also found that mutations in the KDM4 family are associated with neurodevelopmental diseases, but other sites of histone demethylation, by KDM4B, are not known. Based on our previous findings, I hypothesize that the H3K23me3-KDM4B interaction protects chromatin of differentiating neurons against DNA damage during differentiation. This project aims to unravel the molecular mechanisms surrounding the chromatin dynamics of differentiating mammalian neurons. My overall goal of this proposal is to better understand the roles of H3K23me3 and KDM4B during neuronal differentiation.

项目总结/文摘