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

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

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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.

抽象的基因表达的表观遗传调节是通过DNA和相关组蛋白的遗传变化发生的。这种修饰，包括甲基化，乙酰化和核小体重新定位，具有主要和在发展和疾病中的作用知之甚少。最近的研究已经开始探讨听力和平衡疾病，对生活质量产生负面影响并施加重要的社会经济负担数百万美国人。在患有听力或平衡障碍的儿童和成人中人工耳蜗上皮，前庭上皮和相关的神经元经常受到干扰。在内耳期间发育，来自耳囊泡的神经感觉祖细胞会引起感觉毛细胞和前庭神经元。经常发育的基因突变和表观遗传变化导致毛细胞和神经元形成不当，导致听力损失。染色体构酶DNA 结合蛋白7（CHD7）是与内耳有关的ATP依赖性表观遗传染色质重塑剂发展。 CHD7的突变引起电荷综合征（眼骨，心脏缺陷，闭锁 Choanae，增长和发展的迟缓，生殖器性下降和青春期延迟以及耳朵异常）。 CHD7损失的患者经常被诊断出混合导电和感觉性听力损失;但是，尚不清楚引起感觉神经性听力丧失的致病机制。在内部 EAR，CHD7在神经感觉祖细胞，间充质，感觉上皮和其他中动态表达耳细胞类型。但是，尚不清楚哪种耳细胞类型和哪种类型的顺式调节元件是在有致病性CHD7突变的情况下扰动。此外，CHD7已被证明重新定位体外的核小体，但是在眼部发育过程中，chd7的染色质重塑活性尚未已确定。在不同的顺式调节元件上富集CHD7是细胞类型的依赖性的，我们的初步研究已经确定了CHD7与长期非编码RNA转录本的启动子的结合永生的多能耳祖细胞（IMOPS）中的神经元分化。我们假设CHD7形成在耳神经祖细胞中的染色质重塑复合物，并与顺式调节元件结合调节转录。我们将使用小鼠遗传学，单细胞的组合检验假设测序方法和超分辨率显微镜。这些研究的结果将有助于确定感官听力损失的基础机制，增强对内部表观遗传调节的理解耳朵神经感觉细胞的开发，并有助于帮助设计再生或恢复内耳的疗法。