Epigenetic mechanism of histone modifying enzymes in craniofacial development

组蛋白修饰酶在颅面发育中的表观遗传机制

基本信息

批准号：
9529997
负责人：
Karl Bryan Shpargel
金额：
$ 15.55万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9529997
关键词：
Acetylesterase Anterior Area Biochemical Biological Assay Biology Cartilage Cephalic Chemicals Chromatin Chromatin Remodeling Factor Chromatin Structure Data Development Disease Embryo Enhancers Environment Enzyme Inhibitor Drugs Enzymes Epigenetic Process Etiology Excision Face Functional disorder Future Gene Expression Genes Genetic Genetic Transcription Genomic approach Genomics Histologic Histone H3 Histones Human Investigation Kabuki Make-Up Syndrome Knock-out Lysine Maps Methylation Methyltransferase Modeling Molecular Multipotent Stem Cells Mus Mutant Strains Mice Mutate Mutation Neural Crest Neural Crest Cell Pathogenesis Pathogenicity Pathway interactions Patients Phenotype Play Positioning Attribute Post-Translational Protein Processing Proteins Regulatory Pathway Research Resolution Role Shapes Signal Pathway Specific qualifier value Stem cells Structure Syndrome Therapeutic Tissues Transcriptional Activation base craniofacial craniofacial development craniofacial disorder craniofacial structure design epigenomics experimental study face bone structure gene repression histone methyltransferase histone modification loss of function mammalian embryology migration mutant novel promoter protein complex stem cell biology stem cell population synergism

项目摘要

Project Summary Histone post-translational modifications regulate chromatin structure and accessibility to facilitate transcriptional activation or repression of neighboring genes. Countless aspects of organismal development and differentiation rely upon change in chromatin environment to regulate gene activity. The enzymes that catalyze addition or removal of histone modifications offer plasticity to alter chromatin states and gene expression during changes in cellular identity. Appropriate craniofacial development is largely dependent on cranial neural crest stem cell biology. This multi-potent stem cell population is specified in early mammalian embryology for migration to anterior facial positions and directed differentiation towards all facial bone and cartilage. Chromatin-modifying factors play important roles in neural crest transcriptional transitions as mutations in several histone modifying or remodeling enzymes underlie pathogenesis of human craniofacial disorders. One of these disorders, Kabuki syndrome, is caused by mutations in either a histone H3 lysine 27 demethylase (UTX) or a histone H3 lysine 4 methylase (KMT2D). UTX and KMT2D associate biochemically, thus coordinated removal of repressive H3K27 methylation and addition of active H3K4 methylation may regulate neural crest transcriptional activation and facial structure. The experiments outlined in this proposal utilize mouse genetics to model KMT2D neural crest function in the Kabuki craniofacial disorder. Histological, cellular, and genomic approaches will elucidate the cellular and molecular mechanisms of chromatin factors in disease pathogenesis.

项目摘要组蛋白翻译后修饰调节染色质结构和可及性以促进相邻基因的转录激活或抑制。无数生物发展的方面分化依赖于染色质环境的变化来调节基因活性。酶催化组蛋白修饰的添加或去除为改变染色质状态和基因提供可塑性细胞身份变化期间的表达。适当的颅面发育在很大程度上取决于颅神经rest干细胞生物学。在早期的哺乳动物中指定了这种多作用的干细胞种群迁移到前面部位置的胚胎学，并将分化为所有面部骨骼和软骨。染色质修改因子在神经rest的转录转变中起着重要作用人类颅面的发病机理的几种组蛋白修饰或重塑酶的突变疾病。这些疾病之一是Kabuki综合征，是由组蛋白H3赖氨酸的突变引起的27 脱甲基酶（UTX）或组蛋白H3赖氨酸4甲基酶（KMT2D）。 UTX和KMT2D在生化上，因此，协调的去除抑制性H3K27甲基化并添加活性H3K4甲基化可能调节神经rest的转录激活和面部结构。该提案中概述的实验利用小鼠遗传学来对KMT2D神经rest功能进行建模，以模拟Kabuki颅面疾病。组织学细胞和基因组方法将阐明染色质因子的细胞和分子机制疾病发病机理。