Developmental Mechanisms of the Chromodomain Gene Chd7

染色质结构域基因 Chd7 的发育机制

• 批准号: 8580397
• 负责人: Donna M. Martin
• 金额: $ 45.05万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8580397
• 关键词: Autistic Disorder; Binding; Binding Sites; Biology; Blindness; Brain; CHARGE syndrome; Cell Proliferation; Cells; ChIP-seq; Chromatin; Cognition; Coloboma; Congenital Heart Defects; DNA Binding; Data; Defect; Dependence; Development; Diagnosis; Disease; Dose; Dysplasia; Ear; Embryo; Enhancers; Epigenetic Process; Epithelial; Equilibrium; Eye; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Enhancer Element; Genital system; Genome; Growth and Development function; Hearing; Hearing Impaired Persons; Histones; Human; Immunofluorescence Immunologic; Impairment; In Situ Hybridization; Individual; Intellectual functioning disability; Klinefelter' s Syndrome; Knockout Mice; Laboratories; Labyrinth; Longevity; Mammalian Cell; Mediating; Mediator of activation protein; Metabolism; Morphology; Mus; Mutant Strains Mice; Mutation; Neural Crest Cell; Neurocognitive; Neuronal Differentiation; Neurons; Nose; Nuclear; Olfactory Epithelium; Pain; Perception; Phenotype; Population; Prosencephalon; Proteins; RNA Interference; RXR; Regenerative Medicine; Retinoic Acid Receptor; Reverse Transcriptase Polymerase Chain Reaction; Sensory; Sensory Disorders; Signal Pathway; Signal Transduction; Signaling Pathway Gene; Skeleton; Smell Perception; Staging; Stem cells; Structure; Taste Perception; Testing; Tissues; Transcription Initiation Site; Tretinoin; Up-Regulation; Usher Syndrome; Vision; Vitamin A; Vitamin A Deficiency; Wild Type Mouse; Xenopus; base; cardiogenesis; chromatin remodeling; citral; craniofacial; deafness; design; disability; embryo tissue; fetal isotretinoin syndrome; functional restoration; improved; induced pluripotent stem cell; inhibitor/antagonist; malformation; migration; mouse model; mutant; nerve stem cell; neurodevelopment; neurogenesis; preclinical study; prenatal; prevent; public health relevance; regenerative therapy; relating to nervous system; research study; small hairpin RNA; subventricular zone; therapy design; transcriptome sequencing

DESCRIPTION (provided by applicant): Combined impairments in hearing, vision, olfaction, and pain perception are a major contributor to neurocognitive disabilities and adaptive functioning worldwide. Nearly one-third of the population suffers from sensory disorders involving taste, smell, hearing, or balance in their lifetime. Current treatments for congenital or acquired sensory impairments are strictly supportive, and there is a critical unmet need for the development of regenerative therapies. CHARGE Syndrome is a multiple sensory disorder second only to Usher Syndrome as a cause of deaf blindness. CHARGE is characterized by ocular coloboma, heart defects, atresia of the choanae, retardation of growth and development (including intellectual disability and autism), genital hypoplasia (including hypogonadotropic hypogonadism), and ear defects including deafness and inner ear dysplasia. CHARGE is caused by heterozygous mutations in the CHD7 gene encoding a DNA binding ATP- dependent chromatin remodeling protein. Study of CHD7 function is relevant for multiple sensory disorders, as it is highly expressed during development and in mature ear, eye, nasal, craniofacial, brain, and craniofacial tissues. CHD7 binds to methylated histones at enhancer sequences and transcription start sites throughout the genome, in a tissue and developmental stage-specific manner. Current challenges include identification of important target genes and signaling pathways that mediate the cellular effects of CHD7, and determination of whether mammalian CHD7 deficiency phenotypes can be prevented or reversed. Our laboratory has studied mouse models of CHARGE Syndrome and found that CHD7 is a major positive regulator of neural stem cell proliferation in the olfactory epithelium, inner ear, and forebrain subventricular zone. Interestingly, there is significant overlap in phenotypes between CHARGE Syndrome, retinoic acid embryopathy, and vitamin A deficiency in both humans and mice, raising the possibility that control of vitamin A levels may influence CHD7 effects. Preliminary data indicate that altered retinoic acid signaling partially rescues Chd7 heterozygous null phenotypes, suggesting CHD7 and retinoic acid function through common signaling pathways. We have developed the global hypothesis that CHD7 and retinoic acid signaling share common mechanisms or genetic targets that are necessary for proper development of craniofacial structures and neural stem cell proliferation. We propose four aims to test this hypothesis: (1) Determine whether up-regulation of retinoic acid signaling is an essential component of the phenotypes observed in Chd7 deficient mice, (2) Evaluate CHD7- dependence of retinoic acid signaling in proliferation of mouse neural progenitors, (3) Identify common retinoic acid signaling and CHD7 binding sites in neural stem cells, and (4) Test recently generated human induced pluripotent stem cells from CHD7-mutation positive CHARGE individuals for retinoic acid dependent proliferation and differentiation. Results will identify basic mechanisms of chromatin-mediated gene expression in mammalian cells and help establish a basis for the rationale design of pre-clinical trials.

描述（由申请人提供）：听力、视力、嗅觉和疼痛感知的综合障碍是全世界神经认知障碍和适应性功能的主要原因。近三分之一的人口一生中患有涉及味觉、嗅觉、听觉或平衡的感觉障碍。目前治疗先天性或 获得性感觉障碍是严格支持性的，并且再生疗法的开发存在着未满足的关键需求。电荷综合症是一种多种感觉障碍，仅次于亚瑟综合症，是导致聋哑人失明的第二大原因。 CHARGE 的特点是眼部缺损、心脏缺陷、后鼻孔闭锁、生长发育迟缓（包括智力障碍和自闭症）、生殖器发育不全（包括促性腺激素低下性腺功能减退症）以及耳部缺陷（包括耳聋和内耳发育不良）。 CHARGE 是由编码 DNA 结合 ATP 依赖性染色质重塑蛋白的 CHD7 基因杂合突变引起的。 CHD7 功能的研究与多种感觉障碍相关，因为它在发育过程中以及成熟的耳、眼、鼻、颅面、脑和颅面组织中高度表达。 CHD7 以组织和发育阶段特异性的方式在整个基因组的增强子序列和转录起始位点与甲基化组蛋白结合。当前的挑战包括鉴定介导CHD7细胞效应的重要靶基因和信号通路，以及确定是否可以预防或逆转哺乳动物CHD7缺陷表型。我们实验室研究了CHARGE综合征小鼠模型，发现CHD7是嗅上皮、内耳和前脑室下区神经干细胞增殖的主要正调节因子。有趣的是，在人类和小鼠中，CHARGE 综合征、视黄酸胚胎病和维生素 A 缺乏之间的表型存在显着重叠，这增加了控制维生素 A 水平可能影响 CHD7 效应的可能性。初步数据表明，改变的视黄酸信号传导部分挽救了 Chd7 杂合无效表型，表明 CHD7 和视黄酸通过共同的信号传导途径发挥作用。我们提出了一个整体假设，即 CHD7 和视黄酸信号传导具有共同的机制或遗传目标，这些机制或遗传目标对于颅面结构的正常发育和神经干细胞增殖是必需的。我们提出四个目的来检验这一假设：(1) 确定视黄酸信号传导的上调是否是 Chd7 缺陷小鼠中观察到的表型的重要组成部分，(2) 评估小鼠神经祖细胞增殖中视黄酸信号传导的 CHD7 依赖性，(3) 识别神经干细胞中常见的视黄酸信号传导和 CHD7 结合位点，以及 (4) 测试最近生成的人类诱导的 来自 CHD7 突变阳性 CHARGE 个体的多能干细胞，用于视黄酸依赖性增殖和分化。结果将确定哺乳动物细胞中染色质介导的基因表达的基本机制，并有助于为临床前试验的合理设计奠定基础。