Functions of chromatin remodeler Chd7 in retinal cell development

CHD7(Chromodomain helicase DNA-binding7)是一种依赖ATP的染色质 在神经发生和神经脊细胞中具有关键功能的重塑蛋白 发展。CHD7的致病变异是引起电荷的最常见原因 综合征或CHD7障碍，一种复杂的遗传综合征，以眼部为特征 缺损、心脏异常、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。尽管有些人 研究已经研究了早期眼睛缺陷(如 由CHD7致病变异体引起)，目前尚不清楚是否存在 一旦眼形态发生，发育中的视网膜对CHD7的持续需求 完成。我们最近发现CHD7在新基因的子集中强健表达 分化的视网膜细胞类型，包括视杆细胞和视锥细胞，以及 正在增殖的视网膜祖细胞。此外，斑马鱼和小鼠CHD7突变体 视锥感光细胞数目减少和异常小的感光细胞 外部节段，提示CHD7在光感受器分化和 外节形态发生。我们假设染色质重塑功能 CHD7是促进视网膜细胞基因转录激活所必需的 类型分化和参与光感受器外节形态发生的基因。 在这项提议中，我们将通过斑马鱼和 小鼠遗传学、转录和表观基因组分析以及人类视网膜研究 有机物和人类视网膜成像。这些研究的结果将有助于我们的 对视网膜细胞类型发育的遗传和表观遗传调控的理解 以及与CHD7疾病相关的视觉系统缺陷的发病机制。

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.