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R. C. Rao, K. T. Tchedre, N. Coleman, Y. Fang, D. Chen; Histone Lysine Methylation in the Retina. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5944.
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Histone methyltransferases (HMTases) catalyze lysine (K) methylation (HKM) marks on histone tails and represent an important epigenetic mechanism that establishes cell-specific gene expression and functions in development. However, epigenetic control of retinal development is poorly understood. This study was conducted to assess the pattern of HKM expression and functional roles of HMTases in murine retinal cells.
Retinal sections and lysates from embryonic day 14 through adult were processed for immunohistochemistry and immunoblotting using antibodies against various marks and HMTases. To further analyze biological functions of HMTases, the effects of small-molecule inhibitors of HMTases were examined in in vitro.
Two histone marks, histone H3 trimethyl K27 (H3K27me3) and H3K4me3, which localize to euchromatin, are expressed in the nuclear periphery of adult photoreceptors but are distributed throughout the nucleus in all other retinal cell types. The HMTases Ezh2 and G9a, were enriched in the embryonic retina during the period of active retinogenesis. Inhibition of Ezh2 and G9a resulted in retinal ganglion cell (RGC) and Muller glia resulted in marked apoptosis. Ezh2 inhibition resulted in an increase in RGC neurite outgrowth.
Adult murine photoreceptors display a distinct pattern of euchromatic segregation. Epigenetic regulation of gene transcription by Ezh2 and G9a mediated HKM plays crucial roles in retinal cell survival and neurite outgrowth and may represent novel epigenetic targets to enhance viability and axonal regeneration in retinal neurodegenerative diseases such as glaucoma.
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