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

• 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
• 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

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接近性，以促进 转录激活或抑制相邻基因。生物体发展的无数方面 和分化依赖于染色质环境的变化来调节基因活性。的酶 组蛋白修饰催化添加或去除提供了改变染色质状态和基因的可塑性 在细胞身份变化期间表达。适当的颅面发育在很大程度上取决于 脑神经嵴干细胞生物学这种多能干细胞群在早期哺乳动物中被指定为 胚胎学迁移到前面的位置和定向分化向所有面骨， 软骨染色质修饰因子在神经嵴转录转换中起重要作用， 几种组蛋白修饰或重塑酶的突变是人类颅面神经病变发病机制的基础 紊乱这些疾病之一，歌舞伎综合征，是由组蛋白H3赖氨酸27 脱甲基酶（UTX）或组蛋白H3赖氨酸4甲基酶（KMT2D）。UTX和KMT2D在生物化学上结合， 因此，抑制性H3K27甲基化的协同去除和活性H3K4甲基化的添加可以 调节神经嵴转录激活和面部结构。本提案中概述的实验 利用小鼠遗传学来模拟KMT2D神经嵴在歌舞伎颅面疾病中的功能。组织学， 细胞和基因组的方法将阐明细胞和分子机制的染色质因子， 发病机理