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 All these published and unpublished data are shared freely with the biomedical research community through our integrated retinal nucleome database (iRNDb)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 All published and unpublished data are shared through the iRNDb to accelerate discovery on retinal development and disease.

Public Health Relevance

(Relevance Statement): We have developed a fully integrated database that is shared with researchers around the world to help identify the regions of the genome that contribute to complex patterns of gene expression in the retina. Using this database, we identified the first cell-type? and developmental stage?specific core regulatory circuit super- enhancer for a gene that causes microphthalmia when mutated in humans. Discoveries from this study will advance our understanding of complex gene regulation mechanisms that are directly relevant to human retinopathies and bridge a fundamental gap in our knowledge about gene regulation in retinal development and disease.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology of the Visual System Study Section (BVS)
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Greenwell, Thomas
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St. Jude Children's Research Hospital
United States
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