Regulation of Retinal Development via the Epigenetic Modification of Histone H3.
Regulation of Retinal Development via the Epigenetic Modification of Histone H3.
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DOI：
10.1007/978-3-319-17121-0_84
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发表时间：
2016
影响因子：
--
通讯作者：
Sumiko Watanabe;A. Murakami
中科院分区：
文献类型：
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作者：
Sumiko Watanabe;A. Murakami
我们感兴趣的是表观遗传机制在视网膜发育中的作用。通过对不同发育阶段的视网膜提取液进行芯片定量聚合酶链式反应，我们发现在视网膜发育过程中，在视网膜增殖和分化中起关键作用的各个基因上组蛋白H3K27和H3K4的甲基化水平和组蛋白H3的乙酰化水平发生了显著的变化。接下来，我们将重点放在H3K27三甲基化在视网膜发育中的作用。Ezh1和Ezh2是作用于H3K27的甲基转移酶，而Jmjd3和UTx是去甲基酶。我们发现Ezh2和Jmjd3主要在视网膜发育过程中表达，这些基因的功能丧失揭示了H3K27me3在双极细胞亚群成熟中的作用。此外，Ezh2和Jmjd3在Bhlhb4和Vsx1内的特定位置调节H3K27的三甲基化，这在双极细胞亚群的分化中起着关键作用。UTX在视网膜有微弱表达，视网膜组织中的sh-RNA下调UTX的表达，提示UTX也参与了双极细胞的成熟。Ezh1在出生后视网膜有微弱表达，Ezh2基因敲除视网膜的表型表明，Ezh1在视网膜分化后期H3K27的甲基化中起作用。综上所述，我们发现这四个基因在视网膜发育过程中表现出时间和空间上独特的表达模式，通过调控关键遗传位点上的组蛋白H3K27甲基化，在视网膜亚群的分化中发挥关键作用。
We are interested in the roles of epigenetic mechanisms in retinal development. By ChIP-qPCR using whole retinal extracts at various developmental stages, we found that the levels of methylation of histones H3K27 and H3K4 and acetylation of histone H3 at specific loci in various genes, which play critical roles in retinal proliferation and differentiation, changed dramatically during retinal development. We next focused on the roles of H3K27 trimethylation in retinal development. Ezh1 and Ezh2 are methyltransferases that act on H3K27, while Jmjd3 and Utx are demethylases. We found that Ezh2 and Jmjd3 were mainly expressed during retinal development, and a loss-of-function of these genes revealed a role for H3K27me3 in the maturation of subsets of bipolar cells. Furthermore, Ezh2 and Jmjd3 regulate H3K27 trimethylation at specific loci within Bhlhb4 and Vsx1, which play critical roles in the differentiation of subsets of bipolar cells. Utx is expressed weakly in retina, and the down-regulation of Utx by sh-RNA in retinal explants suggested that Utx also participates in the maturation of bipolar cells. Ezh1 is expressed weakly in postnatal retina, and the phenotype of Ezh2-knockout retina suggested that Ezh1 plays a role in the methylation of H3K27 in the late phase of retinal differentiation. Taken together, we found that these four genes, which exhibit temporally and spatially unique expression patterns during retinal development, play critical roles in the differentiation of retinal subsets through the regulation of histone H3K27 methylation at critical genetic loci.