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Genomic studies of CHD7 in CHARGE syndrome

CHARGE 综合征中 CHD7 的基因组研究

基本信息

批准号：
8100186
负责人：
Peter Christopher Scacheri
金额：
$ 30.58万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-20 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8100186
关键词：
11p15 Affect Binding Binding Proteins Binding Sites Biological Assay Body Patterning CHARGE syndrome Cell Culture Techniques Cells Cessation of life Chromatin Chromosomes Clinical Code Coloboma Congenital Abnormality Congenital Heart Defects Cranial Nerves Data Development Disease Ear Embryonic Development Epigenetic Process Equilibrium Ethylnitrosourea Etiology Functional RNA Gene Expression Gene Targeting Genes Genetic Transcription Genomics Growth H19 gene HOXA10 gene Histone H3 Histones Homeobox Genes Human Human Development In Vitro Infant Insulin-Like Growth Factor II Investigation Knowledge Lead Learning Link Location Lysine Maps Mediating Modeling Molecular Molecular Profiling Mus Mutagenesis Mutant Strains Mice Mutation Neural Pathways Nuclear Protein Organ Pathogenesis Pathway interactions Patients Proteins RNA Interference Recombinants Recruitment Activity Research Research Personnel Role Screening procedure Site Specificity Staging Syndrome Techniques Testing Time Transcriptional Regulation Vision body system chromatin immunoprecipitation chromatin modification design embryonic stem cell feeding fetal hearing impairment helicase histone modification human disease imprint in vivo loss of function loss of function mutation malformation mouse model mutant orofacial postnatal premature programs promoter

项目摘要

DESCRIPTION (provided by applicant): CHARGE syndrome is a congenital disease characterized by malformations of multiple organs. ~70% of CHARGE syndrome cases are caused by loss-of-function de novo mutations in the CHD7 gene (coding for chromodomain helicase DMA-binding protein 7). Little information is available about the normal function of the CHD7 protein and its role in human development and disease. Our preliminary studies demonstrate that CHD7 is a nuclear protein that directly binds to multiple genes, including HOX genes (HOXA5, HOXA10, and HOXA11) and imprinted genes (IGF2 and H19) that are essential for normal embryonic development. The proposed research tests the hypothesis that the malformations seen in patients with CHARGE syndrome are caused by aberrant transcription of specific CHD7 target genes. This hypothesis will be tested in 3 Specific Aims. In Aim 1, we will evaluate a subset of the CHD7 target genes to determine if CHD7 directly regulates their expression. Specifically, expression of 50 CHD7 targets will quantified in cell culture before and after knockdown of CHD7 by RNAi. In addition, to determine if anomalies in CHARGE syndrome are due to dysregulated expression of HOX, Igf2, and H19, we will analyze expression of these genes in developing Chd7 mutant mice that are an excellent model CHARGE syndrome. In Aim 2, we will investigate the mechanism by which CHD7 is recruited to its target genes, using in vitro and in vivo assays designed to reveal interactions between CHD7 and various histone modifications on chromatin. In Aim 3, we will identify CHD7 targets that directly depend on CHD7 during early development, using an unbiased genomics approach that combines the technique of chromatin immunoprecipitation on microarrays (ChlP-chip) with expression profiling of wild type and mutant mouse ES cells. By identifying and characterizing the genes that are directly regulated by CHD7, we expect to learn more about (1) normal human development, (2) the causes of the isolated birth defects that make up the spectrum of anomalies in CHARGE, and (3) the etiology of this rare syndrome. In addition to furthering our understanding of the clinical implications of genes regulated by CHD7, we anticipate gaining a significant amount of knowledge about the molecular mechanisms of transcriptional regulation by delineating the interactions between CHD7 and its target genes.

描述（由申请人提供）：