Histone demethylase JHDM2A is critical for Tnp1 and Prm1 transcription and spermatogenesis
Histone demethylase JHDM2A is critical for Tnp1 and Prm1 transcription and spermatogenesis
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DOI：
10.1038/nature06236
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发表时间：
2007-11-01
期刊：
影响因子：
64.8
通讯作者：
Zhang, Yi
中科院分区：
文献类型：
--
作者：
Okada, Yuki;Scott, Greg;Zhang, Yi
最近的研究表明，类似于其他共价修饰，组蛋白赖氨酸甲基化受到酶催化的逆转（1，2）。到目前为止，LSD 1（也称为AOF 2）和含有jumonji C（JmjC）结构域的蛋白质已被证明具有组蛋白脱甲基酶活性。LSD 1通过黄素腺嘌呤二核苷酸依赖性氧化反应催化H3 K4 me 2/H3 K4 me 1的去除（3）。相比之下，含JmjC结构域的蛋白质通过需要α-酮戊二酸和Fe（II）作为辅因子的羟基化反应从组蛋白中去除甲基（4）。虽然越来越多的组蛋白去甲基化酶已被确定和生物化学特征（1，2），其生物学功能，特别是在动物模型的情况下，是不好的特点。在这里，我们使用功能丧失的方法来证明小鼠H3 K9 me 2/1特异性去甲基化酶JHDM 2A（JmjC结构域包含组蛋白去甲基化酶2A，也称为JMJD 1A）是精子发生所必需的。我们发现，Jhdm 2a缺陷小鼠表现出减数分裂后染色质凝聚缺陷，JHDM 2A直接结合并控制过渡核蛋白1（Tnp 1）和鱼精蛋白1（Prm 1）基因的表达，其产物是包装和凝聚精子染色质所必需的。因此，我们的工作揭示了JHDM 2A在精子发生中的作用，并揭示了过渡核蛋白和鱼精蛋白基因作为JHDM 2A的直接靶点。
Recent studies indicate that, similar to other covalent modifications, histone lysine methylation is subject to enzyme-catalysed reversion(1,2). So far, LSD1 (also known as AOF2) and the jumonji C (JmjC)-domain-containing proteins have been shown to possess histone demethylase activity. LSD1 catalyses removal of H3K4me2/H3K4me1 through a flavin-adenine-dinucleotide-dependent oxidation reaction(3). In contrast, JmjC-domain-containing proteins remove methyl groups from histones through a hydroxylation reaction that requires alpha-ketoglutarate and Fe(II) as cofactors(4). Although an increasing number of histone demethylases have been identified and biochemically characterized(1,2), their biological functions, particularly in the context of an animal model, are poorly characterized. Here we use a loss-of-function approach to demonstrate that the mouse H3K9me2/1-specific demethylase JHDM2A (JmjC-domain-containing histone demethylase 2A, also known as JMJD1A) is essential for spermatogenesis. We show that Jhdm2a-deficient mice exhibit post-meiotic chromatin condensation defects, and that JHDM2A directly binds to and controls the expression of transition nuclear protein 1 (Tnp1) and protamine 1 (Prm1) genes, the products of which are required for packaging and condensation of sperm chromatin. Thus, our work uncovers a role for JHDM2A in spermatogenesis and reveals transition nuclear protein and protamine genes as direct targets of JHDM2A.