Epigenetic mechanism of histone modifying enzymes in craniofacial development

项目摘要 组蛋白翻译后修饰调节染色质结构和可及性 邻近基因的转录激活或抑制。生物体发育的无数方面 而分化依赖于染色质环境的变化来调节基因的活性。这些酶可以 组蛋白修饰的催化添加或移除提供了改变染色质状态和基因的可塑性 在细胞身份变化过程中的表达。适当的头面部发育在很大程度上取决于 脑神经脊干细胞生物学。这种多能干细胞群体是早期哺乳动物特有的 胚胎学：迁移到面前位置并定向分化到所有面骨和 软骨。染色质修饰因子在神经脊转录转换中发挥重要作用 几种组蛋白修饰或重塑酶的突变是人类颅面部病变的基础 精神错乱。其中一种疾病，歌舞伎综合症，是由组蛋白H3赖氨酸27的突变引起的 去甲基酶(UTX)或组蛋白H3赖氨酸4甲基酶(KMT2D)。UTX和KMT2D在生物化学上是关联的， 因此，协同去除抑制性H3K27甲基化和添加活性H3K4甲基化可以 调节神经脊转录激活和面部结构。这项提案中概述的实验 利用小鼠遗传学模拟歌舞伎颅面部疾患的KMT2D神经脊功能。组织学上， 细胞和基因组方法将阐明染色质因子的细胞和分子机制。 疾病发病机制。

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.