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Principal Investigator: Michelle Zhang
Organization: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
Fiscal Year: 2024
Award: $30,161
Funding agency: National Eye Institute
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.
Terms: <5' Untranslated Regions><5'UTR><Address><Adverse Late Effects><Affect><Anophthalmia><Anophthalmos><Basal Transcription Factor><Basal transcription factor genes><Binding><Body Tissues><Brachydanio rerio><Cell Body><Cell Differentiation><Cell Differentiation process><Cell Extracts><Cell Line><Cell Reprogramming><CellLine><Cells><ChIP Sequencing><ChIP-seq><ChIPseq><Childhood><Chromatin><Chromatin Remodeling Complex><Chromatin Remodeling Factor><Co-Immunoprecipitations><Complex><Congenital Disorders><Danio rerio><Data><Defect><Degenerative Neurologic Disorders><Dental Pulp><Development><Disease><Disorder><Embryo><Embryonic><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Eye Cancer><Eye Development><Eye diseases><Frame Shift Mutation><Frameshift Mutation><Frog><Gatekeeping><Gene Alteration><Gene Mutation><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Generations><Genes><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Global Change><HD1><HDAC1><HDAC1 gene><HLHX2><Histone Deacetylase 1><Histone H2A><Human><Immunofluorescence><Immunofluorescence Immunologic><In Situ Hybridization><Knowledge><L-Lysine><LH-2><LH2><LHX2><LHX2 gene><LIM HOX Gene 2><LIM Homeo Box Gene 2><LIM Homeobox Gene 2><Late Effects><Link><Lysine><Malignant Eye Neoplasm><Malignant Ocular Neoplasm><Malignant Ocular Tumor><Malignant Tumor of the Eye><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mediating><Microdissection><Microphthalmos><Modeling><Modern Man><Modification><Molecular Interaction><Mutate><Mutation><Nervous System Degenerative Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Non-Polyadenylated RNA><Optic vesicle><Organoids><PRC1><PRC1 Protein><Patients><Persons><Phenotype><Play><Polycomb><Polycomb Repressive Complex 1><Process><Progenitor Cells><Proteins><QOL><Quality of life><RB1><RB1 gene><RNA><RNA Expression><RNA Gene Products><RNA Seq><RNA sequencing><RNAseq><RPD3-Like 1><RPD3L1><Rana><Reading Frame Shift Mutation><Reduced Potassium Dependency 3, Yeast, Homolog-Like 1><Regenerative Medicine><Regulation><Repression><Retina><Retinal Degeneration><Retinal Diseases><Retinal Disorder><Retinal Neuroblastoma><Retinoblastoma><Ribonucleic Acid><Role><Sight><Staining method><Stains><Strains Cell Lines><Syndrome><Testing><Time><Tissues><Transcript><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Variant><Variation><Vision><Visual Fields><Xenopus><Xenopus sp.><Zebra Danio><Zebra Fish><Zebrafish><cell type><cellular differentiation><cellular reprogramming><chromatin immunoprecipitation-sequencing><chromatin modifier><chromatin remodeling><clawed frog><cultured cell line><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><degenerative retina diseases><design><designing><developmental><epigenetic regulation><epigenetically><experiment><experimental research><experimental study><experiments><eye disorder><eye field><eye morphogenesis><gatekeeper><gene network><genome mutation><histone modification><iPS><iPSC><iPSCs><improved><in situ Hybridization Genetics><in situ Hybridization Staining Method><in vitro Model><in vivo><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><knock-down><knockdown><mRNA Leader Sequences><malignant neoplasm of eye><manufacture><microphthalmia><nanophthalmos><neurodegenerative illness><neurogenesis><novel><ocular development><ocular disease><ocular disorder><ophthalmopathy><optic cup><pediatric><progenitor cell gene><progenitor gene><pulp><recruit><regenerative approach><regenerative strategy><regenerative technique><retina degeneration><retina disease><retina disorder><retina neuroblastoma><retinal degenerative><retinal degenerative diseases><retinal progenitor><retinal progenitor cell><retinal stem cell><retinoblastoma-1><retinopathy><social role><stem cell genes><stem cells><transcription factor><transcriptome sequencing><transcriptomic sequencing><visual function>