Functions of chromatin remodeler Chd7 in retinal cell development

染色质重塑蛋白 Chd7 在视网膜细胞发育中的功能

• 批准号: 10675851
• 负责人: Donna M. Martin
• 金额: $ 64.01万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675851
• 关键词: ATAC-seq; Applications Grants; Blindness; Brain; CHARGE syndrome; CHD7 gene; Cells; Childhood; Choanal Atresia; Chromatin; Chromatin Remodeling Factor; Coloboma; Complex; Congenital Abnormality; DNA Binding; Data; Data Set; Defect; Development; Disease; Ear; Embryonic Development; Epigenetic Process; Event; Eye; Eye Abnormalities; Eye Development; Functional disorder; Gene Activation; Gene Expression; Genes; Genetic; Genetic Diseases; Genetic Transcription; Genitourinary system; Growth; Heart; Heart Abnormalities; Human; Image; Individual; Knock-out; Knowledge; Mediating; Molecular; Morphogenesis; Mus; Mutagenesis; Mutation; Neural Crest Cell; Nose; Organoids; Pathogenesis; Pathogenicity; Phenotype; Photoreceptors; Process; Proliferating; Proteins; Retina; Retinal Cone; Role; Structure; Syndrome; Testing; Transcriptional Activation; Variant; Vertebrate Photoreceptors; Vision; Visual System; Visual impairment; Zebrafish; cell type; chromatin remodeling; epigenetic regulation; epigenomics; experience; experimental study; eye formation; gene regulatory network; hearing impairment; helicase; improved; mouse genetics; mouse model; mutant; neurogenesis; novel; retinal imaging; retinal progenitor cell; transcriptome sequencing; transcriptomics

CHD7 (Chromodomain helicase DNA-binding 7) is an ATP-dependent chromatin remodeling protein that has critical functions in neurogenesis and neural crest cell development. Pathogenic variants in CHD7 are the most common cause of CHARGE syndrome or CHD7 disorder, a complex genetic syndrome characterized by ocular coloboma, heart abnormalities, choanal atresia, retardation of growth, genitourinary defects, and hearing loss, as well as other developmental defects. Although some studies have examined the molecular basis for the early ocular defects (such as coloboma) resulting from CHD7 pathogenic variants, it is not known whether there is a continuing requirement for CHD7 in the developing retina once ocular morphogenesis is complete. We have recently shown that CHD7 is robustly expressed in subsets of newly differentiated retinal cell types, including rod and cone photoreceptors, as well as in proliferating retinal progenitor cells. Furthermore, zebrafish and mouse Chd7 mutants display reductions in cone photoreceptor number and abnormally small photoreceptor outer segments, suggesting a critical role for CHD7 in photoreceptor differentiation and outer segment morphogenesis. We hypothesize that the chromatin remodeling function of CHD7 is necessary for the transcriptional activation of genes promoting retinal cell type differentiation and genes involved in photoreceptor outer segment morphogenesis. In this proposal, we will test this hypothesis through a combination of zebrafish and mouse genetics, transcriptomic and epigenomic analyses, and studies of human retinal organoids and human retinal imaging. Results from these studies will contribute to our understanding of the genetic and epigenetic regulation of retinal cell type development as well as the pathogenesis of visual system defects associated with CHD7 disorder.

CHD 7（Chromodomain helicase DNA-binding 7）是一种ATP依赖的染色质 在神经发生和神经嵴细胞中具有关键功能的重塑蛋白 发展CHD 7中的致病性变体是CHARGE的最常见原因。 综合征或CHD 7病症，一种以眼部疾病为特征的复杂遗传综合征， 缺损，心脏畸形，后鼻孔闭锁，生长迟缓，泌尿生殖系统 缺陷，听力损失，以及其他发育缺陷。尽管一些 研究已经检查了早期眼部缺陷（例如， 由于CHD 7致病性变体导致的缺损），尚不清楚是否存在 一旦眼形态发生， 完成.我们最近发现，CHD 7在新发现的 分化的视网膜细胞类型，包括视杆和视锥光感受器，以及 增殖的视网膜祖细胞。此外，斑马鱼和小鼠Chd 7突变体 视锥光感受器数目减少， 外节，表明CHD 7在感光细胞分化中的关键作用， 外节形态发生我们假设染色质重塑功能 CHD 7的转录激活是促进视网膜细胞的基因所必需的 型分化和基因参与感光细胞外节形态发生。 在这项提议中，我们将通过斑马鱼和 小鼠遗传学、转录组学和表观基因组学分析以及人类视网膜病变的研究。 类器官和人类视网膜成像。这些研究的结果将有助于我们 了解视网膜细胞类型发育的遗传和表观遗传调节 以及与CHD 7病症相关的视觉系统缺陷的发病机制。