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Cell-type– and developmental stage–specific regulation of gene expression in the retina

视网膜中基因表达的细胞类型和发育阶段的特异性调控

基本信息

批准号：
9886721
负责人：
Michael A Dyer
金额：
$ 44.88万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
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：
2020-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9886721
关键词：
3-Dimensional Affect Basic Science Binding Binding Sites Biology Biomedical Research Bipolar Neuron Birth Order Cell Death Cell Differentiation process Cell physiology Cells Cellular Structures ChIP-seq Child Chimeric Proteins Chromatin Chromatin Loop Communities Complex Computer Analysis DNA Data Databases Defect Development Disease Elements Enhancers Epigenetic Process Euchromatin Evaluation Foundations Future Gene Expression Gene Expression Profile Gene Expression Regulation Genes Genetic Genetic Enhancer Element Genome Goals Government Heterochromatin Histones Human Individual Knowledge Light Link Maps Mass Spectrum Analysis Medicine Microphthalmos Microscopy Modification Molecular Muller&apos s cell Mus Mutate Neuroglia Organoids Pecans Persons Process Publishing Regulation Regulatory Element Research Research Personnel Research Project Grants Retina Retinal Diseases Retinoblastoma Role Saint Jude Children&apos s Research Hospital Series Slice Structure Study models Testing Transcription Coactivator Transcription Repressor Upstream Enhancer VP 16 Vision cell fate specification cell type cloud based combinatorial data portal data sharing experimental study human embryonic stem cell in utero in vivo insight multidimensional data preservation promoter retinal imaging retinal progenitor cell retinogenesis stem cell proliferation transcription factor tumor

项目摘要

PROJECT SUMMARY During retinal development, more than 8,000 genes change in their expression as multipotent retinal progenitor cells produce each of the 7 classes of cell types in an evolutionarily conserved birth order. Although it has been well established that changes in the covalent modifications to the DNA and histones and higher-order DNA looping accompany changes in gene expression, little is known about how those processes are coordinated during retinal development. Over the past 5 years, we developed a detailed map of the structure and accessibility of the human and mouse retinal genome during development. Specifically, we performed a multifaceted integrated analysis that included profiling of the covalent modifications to the DNA and histones, promoter structure, chromatin accessibility, looping interactions, and euchromatin/heterochromatin localization. All these published and unpublished data are shared freely with the biomedical research community through our integrated retinal nucleome database (iRNDb) (https://pecan.stjude.cloud/retinalnucleome). One of the most significant discoveries to come from the iRNDb was the identification of a series of core regulatory circuit super-enhancers (CRC-SEs) adjacent to genes having important roles in retinal development, including Vsx2, Crx, Six3, Otx2, Fgf15, and Ascl1. The CRC-SE upstream of the Vsx2 gene was particularly exciting because it had activity consistent with bipolar cell development. We deleted the Vsx2-CRC-SE in mice and showed that bipolar neurons are absent yet all other cell types develop normally. Importantly, retinal progenitor cell proliferation was normal, indicating that we had separated the bipolar cell regulatory elements from that of retinal progenitor cells. In this proposal, we will elucidate the structure and organization of the Vsx2 CRC-SE, identify other transcription factors that may cooperate with Vsx2 to regulate bipolar cell type–specific expression and test the consequences of loss of bipolar cells on other cell types in the retina. The results of these studies will be important for filling a fundamental gap in our knowledge about the role of CRC-SEs in retinal development and will set the stage for characterization of CRC-SEs in other genes required for retinogenesis. All published and unpublished data are shared through the iRNDb to accelerate discovery on retinal development and disease.

项目总结