Developmental Mechanisms of the Chromodomain Gene Chd7

染色质结构域基因 Chd7 的发育机制

• 批准号: 8915276
• 负责人: Donna M. Martin
• 金额: $ 6.96万
• 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/8915276
• 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; Health; 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; 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，嗅觉和疼痛感中的综合障碍是全球神经认知障碍和适应性功能的主要贡献者。将近三分之一的人口患有涉及口味，气味，听力或平衡的感觉障碍。先天性或 获得的感官障碍是严格的支持，并且对再生疗法的开发有至关重要的未满足需求。电荷综合征是一种多种感觉障碍，仅是乌瑟综合征的第二种原因。电荷的特征在于眼部coloboma，心脏缺陷，ChoAnae闭锁，生长和发育的延迟（包括智力障碍和自闭症），生殖性下降症（包括性交性性低下性促症）以及耳朵缺陷以及包括聋哑和内耳性不足的耳朵缺陷。电荷是由编码DNA结合ATP染色质重塑蛋白的CHD7基因中的杂合突变引起的。 CHD7功能的研究与多种感觉障碍相关，因为它在发育过程中和成熟的耳朵，眼睛，鼻，颅面，脑，脑和颅面组织都高度表达。 CHD7以增强子序列的甲基化组蛋白结合，并以组织和发育阶段特异性的方式在整个基因组中结合转录起始位点。当前的挑战包括鉴定重要的靶基因和介导CHD7细胞效应的信号传导途径，以及确定是否可以防止或反转哺乳动物CHD7缺乏型表型。我们的实验室研究了电荷综合征的小鼠模型，发现CHD7是嗅觉上皮，内耳和前脑下脑室区域中神经干细胞增殖的主要阳性调节剂。有趣的是，在人和小鼠中，电荷综合征，视黄酸胚胎病和维生素A缺乏之间存在显着重叠，这增加了控制维生素A水平的可能性可能会影响CHD7的影响。初步数据表明，改变视黄酸信号传导部分挽救了CHD7杂合无效表型，这表明CHD7和视黄酸通过共同的信号传导途径。我们已经开发了一个全球假设，即CHD7和视黄酸信号传导具有适当发展颅面结构和神经干细胞增殖所必需的共同机制或遗传靶标。 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来自视黄酸依赖性增殖和分化的CHD7致敬阳性个体的多能干细胞。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理由设计建立基础。