Histone Demethylase Activity of Utx Is Essential for Viability and Regulation of HOX Gene Expression in Drosophila.
Histone Demethylase Activity of Utx Is Essential for Viability and Regulation of HOX Gene Expression in Drosophila.
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DOI：
10.1534/genetics.117.300421
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发表时间：
2018-03
期刊：
影响因子：
3.3
通讯作者：
Müller J
中科院分区：
文献类型：
--
作者：
Copur Ö;Müller J
Polycomb抑制复合物2（PRC2）对组蛋白H3在赖氨酸27（H3K27me3）处的三甲基化对于Polycomb靶基因的抑制是必不可少的。然而，KDM6家族脱甲基酶Utx、Uty和JmjD3对H3K27me3的酶促脱甲基作用尚不清楚。对小鼠和蠕虫的研究表明，KDM6蛋白，而不是其H3K27me3脱甲基酶活性，对正常发育至关重要。在这里，我们调查的要求，在果蝇中的单一KDM6家族成员Utx的脱甲基酶活性。我们产生了表达全长但无催化活性的Utx蛋白的果蝇，并发现这些突变体显示出与缺乏Utx蛋白的动物相同的表型。具体而言，动物缺乏母体沉积的活性Utx去甲基化酶在早期胚胎显示随机损失的HOX基因表达，似乎是在克隆的方式传播。这表明Utx脱甲基酶活性对于在合子基因转录开始期间从活性HOX基因中去除异位H3K27三甲基化是至关重要的，从而防止Polycomb长期抑制的不适当安装。相反，母体沉积的催化活性Utx蛋白足以使缺乏合子表达的酶活性Utx的动物发育成形态正常的成虫，其从蛹壳羽化，但此后不久死亡。因此，Utx脱甲基酶活性对维持成蝇的生存能力也是必不可少的。总之，这些分析确定最早的胚胎阶段和成年阶段的果蝇生命周期中的两个阶段，关键需要H3K27me3去甲基酶活性。
The trimethylation of histone H3 at lysine 27 (H3K27me3) by Polycomb Repressive Complex 2 (PRC2) is essential for the repression of Polycomb target genes. However, the role of enzymatic demethylation of H3K27me3 by the KDM6-family demethylases Utx, Uty, and JmjD3 is less clear. Studies in both mice and worms led to the proposal that KDM6 proteins, but not their H3K27me3 demethylase activity, is critical for normal development. Here, we investigated the requirement of the demethylase activity of the single KDM6 family member Utx in Drosophila. We generated Drosophila expressing a full-length but catalytically inactive Utx protein and found that these mutants show the same phenotypes as animals lacking the Utx protein. Specifically, animals lacking maternally deposited active Utx demethylase in the early embryo show stochastic loss of HOX gene expression that appears to be propagated in a clonal fashion. This suggests that Utx demethylase activity is critical for the removal of ectopic H3K27 trimethylation from active HOX genes during the onset of zygotic gene transcription, and thereby prevents the inappropriate installment of long-term repression by Polycomb. Conversely, maternally deposited catalytically active Utx protein suffices to permit animals that lack zygotic expression of enzymatically active Utx to develop into morphologically normal adults, which eclose from the pupal case but die shortly thereafter. Utx demethylase activity is therefore also essential to sustain viability in adult flies. Together, these analyses identify the earliest embryonic stages and the adult stage as two phases during the Drosophila life cycle that critically require H3K27me3 demethylase activity.