Changes in the Structure and Organization of the Genome During Neurogenesis
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 neurogenesis. 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 (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. Each of those CRC-SEs have been deleted in mice using CRISPR-Cas9 and analysis is ongoing. We are also analyzing the evolutionary conservation of those CRC-SEs in human stem cell derived retinal organoids. 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. We are seeking a highly motivated postdoctoral fellow to study the role of CRC-SEs in retinal development and diseases such as macular degeneration and diabetic retinopathy. Training in epigenetics, retinal biology and human stem cell research is preferred.
Michael A. Dyer, Ph.D.
Chair and Member, Developmental Neurobiology Department
Co-leader Developmental Biology and Solid Tumor Program
St. Jude Children’s Research Hospital
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