During development of the retina, it is critical to precisely coordinate the balance between proliferation and differentiation of progenitors to ensure that the appropriate complement of each cell type is generated. While much has been learned about transcription factors and signaling pathways that regulate this process, there is evidence that epigenetic mechanisms, including histone modifications, play a key role. The polycomb repressive complex 2 (PRC2), catalyzes and maintains methylation of lysine 27 on histone H3, which promotes gene repression. The goal of this proposal is to address the role of PRC2 in the developing retina. We previously found that the PRC2 catalytic subunit EZH2 is critical during postnatal retinal development for maintaining retinal progenitor proliferation, ensuring transcriptional integrity, and coordinating the timing and balance of late retinal cell differentiation. However, it is unclear whether PRC2 plays a role during early retinal neurogenesis, and whether it promotes the maintenance of retinal ganglion cells (RGCs), which are born early during retinal development.
The first aim of the proposal will focus on addressing how PRC2 regulates the differentiation and the maintenance of early born retinal cell types, particularly RGCs.
The second aim will determine how PRC2 activity and target gene selection is regulated by a key accessory protein, JARID2. This work will advance our understanding of how histone modification governs gene expression during retinal neurogenesis. In particular, addressing how a key repressive modification is regulated as RGCs are generated and maintained will be a major step forward. This will help inform strategies for cell replacement in diseases where RGCs degenerate and are lost. In addition, by determining how changes in histone modification contribute to neurodegeneration, we may gain insight into fundamental mechanisms of blinding eye diseases such as glaucoma and other diseases impacting RGCs.
Normal visual function depends upon the generation and maintenance of a balanced complement of retinal cell types, and these processes can be disrupted in pathological situations, including developmental disorders or retinal degeneration. Epigenetic regulation of gene expression is a potent mechanism for governing developmental transitions and for maintaining cellular integrity, but the influence of these mechanisms in the retina is poorly understood. This study will investigate the role of polycomb-mediated gene repression in regulating the genesis, maturation and survival of early-born retinal neurons, particularly retinal ganglion cells.
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