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.

抽象的基因表达的表观遗传调控通过 DNA 和相关组蛋白的可遗传变化发生。此类修饰包括甲基化、乙酰化和核小体重新定位，具有主要和对发育和疾病中的作用知之甚少。最近的研究已经开始探索表观遗传学听力和平衡障碍对生活质量产生负面影响，并对社会经济造成重大影响数百万美国人的负担。在患有听力或平衡障碍的儿童和成人中，耳蜗上皮、前庭上皮和相关神经元经常受到破坏。内耳时在发育过程中，来自耳囊的神经感觉祖细胞产生感觉毛细胞并前庭蜗神经元。经常扰乱耳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。染色质结构域解旋酶 DNA 结合蛋白 7 (CHD7) 是一种与内耳有关的 ATP 依赖性表观遗传染色质重塑蛋白发展。 CHD7 突变会导致 CHARGE 综合征（眼部缺损、心脏缺陷、耳道闭锁）后鼻孔、生长发育迟缓、生殖器发育不全和青春期延迟、耳朵异常）。 CHD7 缺失的患者通常被诊断为混合性传导性听力和感音神经性听力损失;然而，导致感音神经性听力损失的致病机制尚不清楚。在内部耳中，CHD7 在神经感觉祖细胞、间充质、感觉上皮和其他细胞中动态表达耳细胞类型。然而，尚不清楚哪些耳细胞类型以及哪些类型的顺式调节元件因存在致病性 CHD7 突变而受到干扰。此外，CHD7 已被证明可以重新定位体外核小体，但在耳发育过程中，CHD7 在体内的染色质重塑活性尚未得到证实。已确定。 CHD7 在不同顺式调控元件处的富集依赖于细胞类型，我们的初步研究已确定 CHD7 与长非编码 RNA 转录物的启动子结合，永生化多能耳祖细胞（iMOP）中的神经元分化。我们假设 CHD7 形成耳神经感觉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。我们将结合小鼠遗传学、单细胞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音神经性听力损失的机制，增强对内部表观遗传调控的理解耳朵神经感觉细胞的发育，并贡献知识来帮助设计再生或恢复内耳疗法。