Epigenetic regulation, including histone modification, is a critical component of gene regulation, although precisely how this contributes to the development of complex tissues such as the neural retina is still being explored. We show that during retinal development in mouse, there are dynamic patterns of expression of the polycomb repressive complex 2 (PRC2) catalytic subunit EZH2 in retinal progenitors and some differentiated cells, as well as dynamic changes in the histone modification H3K27me3. Using conditional knockout of Ezh2 using either Pax6-αCre or Six3-Cre, we find selective reduction in postnatal retinal progenitor proliferation, disruption of retinal lamination, and enhanced differentiation of several late born cell types in the early postnatal retina, including photoreceptors and Müller glia, which are ultimately increased in number and become reactive. RNA-seq identifies many non-retinal genes upregulated with loss of Ezh2, including multiple Hox genes and the cell cycle regulator Cdkn2a, which are established targets of EZH2-mediated repression. ChIP analysis confirms loss of the H3K27me3 modification at these loci. Similar gene upregulation is observed in retinal explants treated with an EZH2 chemical inhibitor. There is considerable overlap with EZH2-regulated genes reported in non-neural tissues, suggesting that EZH2 can regulate similar genes in multiple lineages. Our findings reveal a conserved role for EZH2 in constraining the expression of potent developmental regulators to maintain lineage integrity and retinal progenitor proliferation, as well as regulating the timing of late differentiation.
Pubmed ID: 25989023 RIS Download
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View all literature mentionsFunctional genomics data repository supporting MIAME-compliant data submissions. Includes microarray-based experiments measuring the abundance of mRNA, genomic DNA, and protein molecules, as well as non-array-based technologies such as serial analysis of gene expression (SAGE) and mass spectrometry proteomic technology. Array- and sequence-based data are accepted. Collection of curated gene expression DataSets, as well as original Series and Platform records. The database can be searched using keywords, organism, DataSet type and authors. DataSet records contain additional resources including cluster tools and differential expression queries.
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