Abstract
Epigenetic predisposition is thought to critically contribute to adult-onset disorders, such as retinal neurodegeneration. The histone methyltransferase, enhancer of zeste homolog 2 (Ezh2), is transiently expressed in the perinatal retina, particularly enriched in retinal ganglion cells (RGCs). We previously showed that embryonic deletion of Ezh2 from retinal progenitors led to progressive photoreceptor degeneration throughout life, demonstrating a role for embryonic predisposition of Ezh2-mediated repressive mark in maintaining the survival and function of photoreceptors in the adult. Enrichment of Ezh2 in RGCs leads to the question if Ezh2 also mediates gene expression and function in postnatal RGCs, and if its deficiency changes RGC susceptibility to cell death under injury or disease in the adult. To test this, we generated mice carrying targeted deletion of Ezh2 from RGC progenitors driven by Math5-Cre (mKO). mKO mice showed no detectable defect in RGC development, survival, or cell homeostasis as determined by physiological analysis, live imaging, histology, and immunohistochemistry. Moreover, RGCs of Ezh2 deficient mice revealed similar susceptibility against glaucomatous and acute optic nerve trauma-induced neurodegeneration compared to littermate floxed or wild-type control mice. In agreement with the above findings, analysis of RNA sequencing of RGCs purified from Ezh2 deficient mice revealed few gene changes that were related to RGC development, survival and function. These results, together with our previous report, support a cell lineage-specific mechanism of Ezh2-mediated gene repression, especially those critically involved in cellular function and homeostasis.
Highlights
Epigenetic predisposition in the embryo is reported to regulate postnatal cell homeostasis and gene expression [1]; its disruption contributes critically to the progression of neurodegenerative disorders in adults [2]
In agreement with the reports that ~50% retinal ganglion cells (RGCs) were positive for Cre detection in Math5-cre mice [27], our result confirmed that some RGCs of mKO mice retained H3K27me3 signals
By selectively deleting enhancer of zeste homolog 2 (Ezh2) from Math5+ lineage progenitors driven through Math5-Cre in the present study, we showed that absence of Ezh2 in the perinatal period has little impact on the expression of retinal specific genes or its direct target genes identified in photoreceptor progenitors, such as Six1 [8]
Summary
Epigenetic predisposition in the embryo is reported to regulate postnatal cell homeostasis and gene expression [1]; its disruption contributes critically to the progression of neurodegenerative disorders in adults [2]. Emerging evidence suggests that gene loci linked with retinal. Ezh does not mediate retinal ganglion cell homeostasis. Foundation of Guangdong Province (2016A030310201) to L.C and Massachusetts Lions Eye Research Fund to DFC. The funders did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript
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