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Ryoji Yamazaki, Kimiko Katoh, Rikako Sanuki, Takahisa Furukawa; G9a Histone Methyltransferase Activity in Retinal Progenitors is Essential for Proper Differentiation and Survival of Mouse Retinal Cells. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3749.
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© ARVO (1962-2015); The Authors (2016-present)
To examine the influence of histone modification on mouse retinal development, we searched for chromatin modifying enzymes by investigating microarray data sets from various stages of retinal development. In this screen, we found that G9a, a histone modification enzyme that preferentially produces H3K9me2, is substantially expressed throughout retinal development. DNA methylation and methylation of histones, especially at H3K9, are well known marks associated with stable gene repression.
To clarify the role of G9a during retinal development, we generated G9a Dkk3 conditional knock-out (CKO) mice in retinal progenitor cells by mating G9aflox mice with Dkk3-Cre mice in which Cre recombinase-mediated recombination occurs in almost all retinal progenitor cells. We performed immunohistochemical analysis to observe histology of the G9a Dkk3 CKO retina. We also performed microarray and Q-PCR analyses to compare gene expression between the control and G9a Dkk3 CKO retinas at P6. Furthermore, to elucidate G9a function in cell differentiation, we focused on photoreceptors. We generated G9a Crx CKO mice and anlyzed their retina.
G9a Dkk3 CKO mice showed thinner retinal layers and abundant rosette structures. In the G9a Dkk3 CKO retina, cell death was markedly increased through developing stages, and abnormal retinal cell proliferation at postnatal stages was observed. We also observed perturbed development of retinal cells in G9a Dkk3 CKO mice. In contrast, the G9a Crx CKO retina showed almost normal development, suggesting that severe abnormalities of the G9a Dkk3 CKO retina were caused mainly by the loss of H3K9me2 marks on the promoters of progenitor cell-related genes in retinal progenitor cells.
Our study shows that epigenetic regulation by G9a in retinal progenitor cells plays an essential role for proper retinal development by silencing progenitor genes in terminal differentiation. The establishment of H3K9me2 marks in retinal progenitor cells is crucial for normal development and appears to serve as an epigenetic memory of the differentiated state.
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