Ezh2 does not mediate retinal ganglion cell homeostasis or their susceptibility to injury.
Ezh2 does not mediate retinal ganglion cell homeostasis or their susceptibility to injury.
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DOI：
10.1371/journal.pone.0191853
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Chen DF
中科院分区：
文献类型：
--
作者：
Cheng L;Wong LJ;Yan N;Han RC;Yu H;Guo C;Batsuuri K;Zinzuwadia A;Guan R;Cho KS;Chen DF
表观遗传易感性被认为是成人发病疾病的关键因素，如视网膜神经变性。组蛋白甲基转移酶是ZEST同源物2(Ezh2)的增强子，在围生期视网膜中瞬时表达，尤其是在视网膜神经节细胞(RGCs)中表达丰富。我们先前的研究表明，胚胎中Ezh2从视网膜前体细胞中的缺失会导致整个生命过程中光感受器的进行性退化，这表明Ezh2介导的抑制标记在维持成年视网膜光感受器的存活和功能方面具有胚胎易感性的作用。Ezh2在RGCs中的丰富导致了这样的问题：Ezh2是否也介导了出生后RGCs的基因表达和功能，以及它的缺失是否改变了RGC在损伤或疾病下对细胞死亡的易感性。为了测试这一点，我们产生了携带由Math5-CRE(MKO)驱动的RGC祖细胞的Ezh2靶向缺失的小鼠。生理分析、活体成像、组织学和免疫组织化学结果显示，MKO小鼠在RGC发育、存活或细胞稳态方面没有可检测到的缺陷。此外，Ezh2基因缺陷小鼠的视网膜节细胞对青光眼和急性视神经损伤引起的神经变性的易感性与斜坡型或野生型对照小鼠相似。从Ezh2基因缺陷小鼠纯化的RGC的RNA序列分析显示，与RGC的发育、存活和功能相关的基因变化很少，这与上述发现一致。这些结果与我们之前的报告一起，支持Ezh2介导的基因抑制的细胞系特异性机制，特别是那些关键涉及细胞功能和动态平衡的机制。
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.
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