Epigenetic Regulation of Retinal Development by BCOR

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Project Summary Normal vision depends on the balanced generation and homeostatic regulation of major retinal cell types, and the disruption of these processes may result in congenital retinal disorders and retinal degeneration, affecting millions of people around the world each year. Regenerative medicine depends on our understanding of retinal development for informing retinal cell reprogramming and manufacturing. While there have been significant advances in unravelling the roles of transcription factors, a major gap exists in our knowledge of how these tightly regulated gene networks are governed by epigenetic mechanisms. Polycomb-group complexes are evolutionarily conserved epigenetic machineries that remodel chromatin through histone modifications for silencing targeted genes and have been recently shown to affect retinal neurogenesis and lineage decisions. BCOR is a component of the Polycomb Repressive Complex 1 variant that ubiquitinates lysine 119 on histone H2A (H2AK119Ub). Dysregulation of BCOR is clearly associated with eye and retinal disorders, including Lenz microphthalmia, Oculofaciocardiodental Syndrome, and retinoblastoma, but its role in retinal neurogenesis is still not well understood. In preliminary studies, I performed coimmunoprecipitation-mass spectrometry and validated BCOR’s interaction with other PcG proteins in retinal cells. I then performed BCOR chromatin immunoprecipitation sequencing (ChIP-seq) and identified strong peaks at retinal progenitor genes LHX2, PAX6, SIX3, and SIX6, all of which are significant in optic vesicle development and later play distinct roles in retinal cell fate decisions. Thus, I propose to investigate the role of BCOR in retinal neurogenesis. I hypothesize that BCOR mediates the switch from retinal progenitors to differentiated cell types by recruiting PcG proteins to regulate H2AK119Ub on the chromatin to repress multipotency genes. I will test this hypothesis with the following aims: (1) Identify the epigenetic mechanism of BCOR for regulating retinal progenitor genes, and (2) Determine how BCOR affects the generation of major retinal cell types in vivo. My overall objective is to characterize BCOR-ncPRC1.1’s role in retinal development as an avenue to discovering new epigenetic targets for regenerative strategies in the retina.