Jmjd5, an H3K36me2 histone demethylase, modulates embryonic cell proliferation through the regulation of Cdkn1a expression
Jmjd5, an H3K36me2 histone demethylase, modulates embryonic cell proliferation through the regulation of Cdkn1a expression
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DOI：
10.1242/dev.074138
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发表时间：
2012-02-15
期刊：
影响因子：
4.6
通讯作者：
Suzuki, Takeshi
中科院分区：
文献类型：
--
作者：
Ishimura, Akihiko;Minehata, Ken-ichi;Suzuki, Takeshi
组蛋白的共价修饰在染色质结构和动力学中起着重要作用。特别是，组蛋白赖氨酸甲基化在不同的生物过程中对于转录控制是重要的。核蛋白Jmjd5(又称Kdm8)是一种组蛋白赖氨酸去甲基酶，在C-末端含有一个JmjC结构域。在本研究中，我们建立了Jmjd5缺陷小鼠(Jmjd5(Delta/Delta))来研究Jmjd5在体内的功能。Jmjd5(Delta/Delta)胚胎表现出严重的生长迟缓，导致胚胎在妊娠中期死亡。来源于Jmjd5亚型胚胎(Jmjd5(neo/neo))的小鼠胚胎成纤维细胞(MEF)也表现出生长缺陷。多种细胞周期调控因子的定量PCR分析表明，只有CDKN1A在Jmjd5(neo/neo)MEF和Jmjd5(Delta/Delta)胚胎中表达上调。CDKN1A特异性小干扰RNA的敲除实验表明，Jmjd5(neo/neo)MEF的生长缺陷被显著挽救。此外，利用Jmjd5(Delta/Delta)；CDKN1A(Delta/Delta)双基因敲除小鼠的遗传学研究表明，CDKN1A缺乏可以部分挽救Jmjd5(Delta/Delta)胚胎的生长迟缓。染色质免疫沉淀分析显示，在Jmjd5(neo/neo)MEF中，组蛋白H3(H3K36me2)的二甲基化赖氨酸36增加，内源性Jmjd5募集减少。综上所述，这些结果表明，Jmjd5通过表观遗传调控CDKN1A的表达，在生理上调节胚胎细胞的增殖。
Covalent modifications of histones play an important role in chromatin architecture and dynamics. In particular, histone lysine methylation is important for transcriptional control during diverse biological processes. The nuclear protein Jmjd5 (also called Kdm8) is a histone lysine demethylase that contains a JmjC domain in the C-terminal region. In this study, we have generated Jmjd5-deficient mice (Jmjd5(Delta/Delta)) to investigate the in vivo function of Jmjd5. Jmjd5(Delta/Delta) embryos showed severe growth retardation, resulting in embryonic lethality at the mid-gestation stage. Mouse embryonic fibroblasts (MEFs) derived from Jmjd5 hypomorphic embryos (Jmjd5(neo/neo)) also showed the growth defect. Quantitative PCR analysis of various cell cycle regulators indicated that only Cdkn1a expression was upregulated in Jmjd5(neo/neo) MEFs and Jmjd5(Delta/Delta) embryos. A knockdown assay with Cdkn1a-specific small interfering RNAs revealed that the growth defect of Jmjd5(neo/neo) MEFs was significantly rescued. In addition, a genetic study using Jmjd5(Delta/Delta); Cdkn1a(Delta/Delta) double-knockout mice showed that the growth retardation of Jmjd5(Delta/Delta) embryos was partially rescued by Cdkn1a deficiency. Chromatin immunoprecipitation analysis showed that increased di-methylated lysine 36 of histone H3 (H3K36me2) and reduced recruitment of endogenous Jmjd5 were detected in the transcribed regions of Cdkn1a in Jmjd5(neo/neo) MEFs. Taken together, these results suggest that Jmjd5 physiologically moderates embryonic cell proliferation through the epigenetic control of Cdkn1a expression.