Dynamic Patterns of Histone Lysine Methylation in the Developing Retina
Dynamic Patterns of Histone Lysine Methylation in the Developing Retina
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DOI：
10.1167/iovs.09-4730
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发表时间：
2010-12-01
影响因子：
4.4
通讯作者：
Chen, Dong Feng
中科院分区：
文献类型：
--
作者：
Rao, Rajesh C.;Tchedre, Kissaou T.;Chen, Dong Feng
目的.组蛋白赖氨酸甲基化（HKM）是一种重要的表观遗传学机制，在发育中建立细胞特异性基因表达和功能。然而，视网膜发育的表观遗传控制知之甚少。为了研究HKM在视网膜发生中的作用，作者检测了小鼠视网膜中三种HKM修饰及其两种调节剂组蛋白甲基转移酶（HMTases）Ezh 2和G9 a的动态变化。从胚胎第16天到成人的视网膜切片和裂解物被处理用于免疫组织化学和免疫印迹，使用针对各种标记和HMT酶的抗体。为了进一步分析HKM的生物学功能，在体外检查了HMT酶的小分子抑制剂的作用。甲基化标记的三甲基赖氨酸4和27组蛋白H3（H3 K4 me 3和H3 K27 me 3）主要在分化的视网膜神经元在胚胎和成人视网膜。与此相反，二甲基赖氨酸9组蛋白H3（H3 K9 me 2）注意到在早期分化的视网膜神经节细胞，但出生后丢失。H3 K27 me 3，H3 K9 me 2，Ezh 2和G9 a的HMTases控制丰富的内胚视网膜活跃的视网膜发生期间。使用Ezh 2和G9 a的化学抑制剂，作者揭示了HKM在调节视网膜神经元存活中的作用。HKM是视网膜发育过程中一个动态的、时空调控的过程。Ezh 2和G9 a介导的HKM对基因转录的表观遗传调控在视网膜神经元存活中起着至关重要的作用，并且可能代表了新的表观遗传靶点，以增强视网膜神经退行性疾病如青光眼的生存能力。（Invest Ophthalmol维斯科学。2010;51：6784-6792）DOI：10.1167/iovs.09-4730
PURPOSE. Histone lysine methylation (HKM) is an important epigenetic mechanism that establishes cell-specific gene expression and functions in development. However, epigenetic control of retinal development is poorly understood. To study the roles of HKM in retinogenesis, the authors examined the dynamic changes of three HKM modifications and of two of their regulators, the histone methyltransferases (HMTases) Ezh2 and G9a, in the mouse retina.METHODS. Retinal sections and lysates from embryonic day 16 through adult were processed for immunohistochemistry and immunoblotting using antibodies against various marks and HMTases. To further analyze the biological functions of HKM, the effects of small molecule inhibitors of HMTases were examined in vitro.RESULTS. Methylation marks of trimethyl lysine 4 and 27 on histone H3 (H3K4me3 and H3K27me3) were detected primarily in differentiated retinal neurons in the embryonic and adult retina. In contrast, dimethyl lysine 9 on histone H3 (H3K9me2) was noted in early differentiating retinal ganglion cells but was lost after birth. The HMTases controlling H3K27me3, H3K9me2, Ezh2, and G9a were enriched in the inner embryonic retina during the period of active retinogenesis. Using the chemical inhibitors of Ezh2 and G9a, the authors reveal a role for HKM in regulating retinal neuron survival.CONCLUSIONS. HKM is a dynamic and spatiotemporally regulated process in the developing retina. Epigenetic regulation of gene transcription by Ezh2- and G9a-mediated HKM plays crucial roles in retinal neuron survival and may represent novel epigenetic targets to enhance viability in retinal neurodegenerative diseases such as glaucoma. (Invest Ophthalmol Vis Sci. 2010;51:6784-6792) DOI:10.1167/iovs.09-4730