title: Ezh2 maintains retinal progenitor proliferation, transcriptional integrity, and the timing of late differentiation.
abstract: 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.
authors.affiliation: Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT, United States.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Biological Structure, University of Washington, Seattle, WA, United States.
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Taylor
authors.affiliation: Department of Biological Structure, University of Washington, Seattle, WA, United States.
authors.forename: Anna
authors.initials: A
authors.lastname: La Torre
authors.affiliation: Department of Biological Structure, University of Washington, Seattle, WA, United States; Molecular and Cellular Biology Program, University of Washington, Seattle, WA, United States.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Wilken
authors.affiliation: Department of Biological Structure, University of Washington, Seattle, WA, United States.
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Cox
authors.affiliation: Department of Biological Structure, University of Washington, Seattle, WA, United States.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Reh
authors.affiliation: Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT, United States. Electronic address: monica.vetter@neuro.utah.edu.
authors.forename: Monica L
authors.initials: ML
authors.lastname: Vetter
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D042002:Chromatin Assembly and Disassembly; D000071221:Enhancer of Zeste Homolog 2 Protein; D005786:Gene Expression Regulation; D051379:Mice; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*; D012160:Retina / Q000166:cytology* / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2
keywords: Histone modification; Neurogenesis; PRC2; Proliferation; Retina