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Naihong Yan, Lin Cheng, Honghua Yu, Kin-Sang Cho, Dongfeng Chen; Epigenetic repression of photoreceptor genes expression by Ezh2 is required for postnatal homeostasis. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4999.
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To elucidate whether the polycomb histone methyltransferase Ezh2 regulates retinal neuron development and function.
The Ezh2 knockout mice line Chx10-cre Ezh2flox/flox was generated to investigate the roles of Ezh2 in retina development and function. The morphology of Chx10-cre Ezh2flox/flox and controls was detected by hematoxylin and eosin (H&E) staining and immunohistochemistry (IHC). The thickness of retinal layers, mainly the outer nuclear layer (ONL) was measured with IHC and spectrum domain-OCT. Mouse retinal functions were assessed by electroretinogram (ERG) in animals aged 1- 12 months. The global gene expression profile of P0 Chx10-cre Ezh2flox/flox mice retina was examined by cDNA microarray, and the levels of expression of various retinal cell markerswere quantitatively assessed by real time RT-PCR. Bioinformatics and ChIP assay were employed to determine the downstream targets and signal events in Ezh2-deficient mice.
The results of H&E, IHC and OCT showed that Chx10-cre Ezh2flox/flox mice exhibited progressive retina degeneration in the postnatal life. In Chx10-cre Ezh2flox/flox mice, retinal layers were substantially thinner than those of the littermate control retinas, and there was a progressive decrease of ONL in the Chx10-cre Ezh2flox/flox mouse retina from 1 - 12 month old. Chx10-cre Ezh2flox/flox mice also displayed progressive functional degeneration as measured by ERG. Significantly decreased ERG a and b wave amplitudes were observed between 1 to 12 month old Chx10-cre Ezh2flox/flox mice while their littermate control mice showed constant normal response of ERG a and b wave. Microarray and RT-PCR suggested that photoreceptor related genes (e.g., Recoverin and Rhodopsin) and the transcription factors Nrl were up-regulate in the retinas of Chx10-cre Ezh2flox/flox mice.
This study indicates that the H3K27me3 histone modification mediated by Ezh2 is essential for retinal development and homeostasis in the postnatal life.
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