权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Epigenetics of inner ear neurosensory cell development

内耳神经感觉细胞发育的表观遗传学

基本信息

批准号：
10430123
负责人：
KELVIN YUI-HANG KWAN
金额：
$ 48.53万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10430123
关键词：
3&apos Untranslated Regions ATAC-seq Acetylation Adult Affect American Binding Brain CHARGE syndrome CHD7 gene CRISPR interference Cardiac Cells Child Chromatin Chromatin Remodeling Factor Cochlea Cognition Coloboma Congenital Disorders DNA DNA-Binding Proteins Development Diagnosis Disease ENG gene Ear Enhancers Epigenetic Process Epithelial Exhibits Fluorescence Resonance Energy Transfer Fluorescent in Situ Hybridization Ganglia Gene Expression Regulation Genes Genetic Transcription Genital Genitalia Growth and Development function Hair Cells Hearing Hearing problem Heart Abnormalities Heritability Histones Human In Situ Hybridization In Vitro Kidney Knowledge Labyrinth Mesenchyme Methylation Microscopy Mixed Conductive-Sensorineural Hearing Loss Modification Mus Mutation Neuronal Differentiation Neurons Nucleic Acid Regulatory Sequences Nucleosomes Optics Otic Vesicle Pathogenicity Pathway interactions Patients Pharmacology Proteins Quality of life Regulatory Element Resolution Role SOX11 gene Sensorineural Hearing Loss Sensory Sensory Hair Stem Cell Development Structure Testing Tissues Transcript Untranslated RNA Variant Vision cell type chromatin remodeling cochlear development craniofacial design ear development environmental change epigenetic regulation equilibration disorder gene therapy hearing impairment in vivo inner ear development mouse genetics neurosensory progenitor promoter reconstruction recruit regenerative single cell sequencing single molecule skeletal socioeconomics stem cells

项目摘要

ABSTRACT Epigenetic regulation of gene expression occurs via heritable changes in DNA and associated histone proteins. Such modifications, which include methylation, acetylation, and nucleosome repositioning, have a major and poorly understood role in development and disease. Recent studies have begun to explore epigenetics of hearing and balance disorders which negatively impact quality of life and impose a significant socioeconomic burden on millions of Americans. In both children and adults with hearing or balance disorders, development of the cochlear epithelium, vestibular epithelia and associated neurons are often disrupted. During inner ear development, neurosensory progenitors from the otic vesicle give rise to sensory hair cells and vestibulocochlear neurons. Mutations and epigenetic changes in genes that perturb otic development often cause improper hair cell and neuron formation, resulting in hearing loss. The chromodomain helicase DNA binding protein 7 (CHD7) is an ATP dependent epigenetic chromatin remodeler implicated in inner ear development. Mutations in CHD7 cause CHARGE syndrome (ocular Coloboma, Heart defects, Atresia of the choanae, Retardation of growth and development, Genital hypoplasia and pubertal delay, and Ear abnormalities). Patients with CHD7 loss are often diagnosed with mixed conductive and sensorineural hearing loss; however, the pathogenic mechanisms that cause sensorineural hearing loss are not known. In the inner ear, CHD7 is dynamically expressed in neurosensory progenitors, mesenchyme, sensory epithelium, and other otic cell types. However, it is unclear which otic cell type(s) and what type of cis-regulatory element(s) are perturbed in the presence of pathogenic CHD7 mutations. In addition, CHD7 has been shown to reposition nucleosomes in vitro, yet the chromatin remodeling activity of CHD7 in vivo during otic development has not been determined. Enrichment of CHD7 at different cis-regulatory elements is cell type dependent, and our preliminary studies have identified CHD7 binding to the promoter of long noncoding RNA transcripts preceding neuronal differentiation in immortalized multipotent otic progenitors (iMOPs). We hypothesize that CHD7 forms a chromatin remodeling complex in otic neurosensory progenitors and binds to cis-regulatory elements to regulate transcription. We will test our hypothesis using a combination of mouse genetics, single-cell sequencing approaches, and super-resolution microscopy. Results from these studies will help identify mechanisms underlying sensorineural hearing loss, enhance understanding of epigenetic regulation of inner ear neurosensory cell development, and contribute knowledge to help design regenerative or restorative therapies for the inner ear.

摘要