Epigenetics of Inner ear neurosensory cell development

内耳神经感觉细胞发育的表观遗传学

• 批准号: 10650504
• 负责人: KELVIN YUI-HANG KWAN
• 金额: $ 14.83万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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/10650504
• 关键词: Acetylation; Adult; Affect; American; Binding; Bioinformatics; Brain; CHARGE syndrome; CHD7 gene; CRISPR interference; Cardiac; Cells; Child; Chromatin Remodeling Factor; Cognition; Coloboma; Congenital Disorders; DNA; Development; Diagnosis; Disease; Ear; Epigenetic Process; Epithelial; Fluorescent in Situ Hybridization; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genital; Genitalia; Goals; Growth and Development function; Hair Cells; Hearing; Hearing problem; Heart Abnormalities; Heritability; Histones; Human; In Vitro; Kidney; Knowledge; Labyrinth; Mesenchyme; Methylation; Microscopy; Minority; Mixed Conductive-Sensorineural Hearing Loss; Modification; Mus; Mutation; National Institute on Deafness and Other Communication Disorders; Neuronal Differentiation; Neurons; Nucleosomes; Otic Vesicle; Pathogenicity; Patients; Pharmacology; Postdoctoral Fellow; Proteins; Quality of life; Regulatory Element; Research; Research Project Grants; Resolution; Role; SOX11 gene; Scientist; Sensorineural Hearing Loss; Sensory; Sensory Hair; Structure; Techniques; Testing; Training; Training Support; Transcript; Untranslated RNA; Variant; Vision; cell type; chromatin remodeling; cochlear development; craniofacial; design; epigenetic regulation; equilibration disorder; gene therapy; hearing impairment; in vivo; inner ear development; mouse genetics; neurosensory; progenitor; promoter; regenerative; single cell sequencing; single molecule; single-cell RNA sequencing; skeletal; socioeconomics; stem cell biology

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 基因表达的表观遗传调控通过DNA和相关组蛋白的遗传变化发生。 这种修饰，包括甲基化、乙酰化和核小体重新定位，具有主要的和重要的生物学功能。 对发育和疾病的作用知之甚少。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、前庭上皮和相关的神经元经常被破坏。在内耳 在发育过程中，来自耳泡的神经感觉祖细胞产生感觉毛细胞， 前庭耳蜗神经元基因的突变和表观遗传变化通常会干扰发育， 导致毛细胞和神经元形成不当，导致听力损失。染色体结构域解旋酶DNA 结合蛋白7（CHD7）是一种与内耳相关的ATP依赖性表观遗传染色质重塑蛋白 发展CHD7中的突变引起CHARGE综合征（眼缺损、心脏缺陷、动脉闭锁）。 慢性乙型肝炎、生长发育迟缓、生殖器发育不全和青春期延迟以及耳 异常）。患有CHD7损失的患者通常被诊断为混合传导性和感音神经性听力 感音神经性听力损失的发病机制尚不清楚。在内 在耳中，CHD7在感觉神经祖细胞、间充质、感觉上皮和其他细胞中动态表达。 耳细胞类型。然而，目前还不清楚哪种耳细胞类型和哪种类型的顺式调节元件， 在致病性CHD7突变的存在下受到干扰。此外，CHD7已被证明重新定位 然而，在耳发育过程中，CHD7在体内的染色质重塑活性并没有 确定了CHD7在不同顺式调节元件处的富集是细胞类型依赖性的，并且我们的研究表明， 初步研究已经鉴定出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（iMOPs）中的神经元分化。我们假设CHD7形成于 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。我们将使用小鼠遗传学、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潜在机制，加强对内分泌系统表观遗传调控的理解。 耳神经感觉细胞的发展，并有助于知识，以帮助设计再生或恢复 内耳的治疗。