PKA-dependent regulation of the histone lysine demethylase complex PHF2-ARID5B
PKA-dependent regulation of the histone lysine demethylase complex PHF2-ARID5B
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DOI：
10.1038/ncb2228
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发表时间：
2011-06-01
影响因子：
21.3
通讯作者：
Kato, Shigeaki
中科院分区：
文献类型：
--
作者：
Baba, Atsushi;Ohtake, Fumiaki;Kato, Shigeaki
可逆组蛋白甲基化和去甲基化是高度调控的过程，对于响应细胞外条件的染色质重组和基因转录调节至关重要。然而，调节组蛋白修饰酶的机制在很大程度上尚不清楚。在这里，我们表征了蛋白激酶 A (PKA) 依赖性组蛋白赖氨酸脱甲基酶复合物 PHF2-ARID5B。 PHF2 是一种 jmjC 去甲基化酶，其本身无酶活性，但通过 PKA 介导的磷酸化变成活性 H3K9Me2 去甲基化酶。我们发现磷酸化的PHF2随后与DNA结合蛋白ARID5B结合，并诱导甲基化的ARID5B去甲基化。这种修饰导致 PHF2 ARID5B 复合物靶向其目标启动子，从而去除抑制性 H3K9Me2 标记。这些发现表明，PHF2 ARID5B 复合物是组蛋白甲基化和基因转录的信号传感调节剂，其中 PHF2 的磷酸化能够随后形成有能力的特异性组蛋白去甲基化酶复合物。
Reversible histone methylation and demethylation are highly regulated processes that are crucial for chromatin reorganization and regulation of gene transcription in response to extracellular conditions. However, the mechanisms that regulate histone-modifying enzymes are largely unknown. Here, we characterized a protein kinase A (PKA)-dependent histone lysine demethylase complex, PHF2-ARID5B. PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. This modification leads to targeting of the PHF2 ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. These findings suggest that the PHF2 ARID5B complex is a signal-sensing modulator of histone methylation and gene transcription, in which phosphorylation of PHF2 enables subsequent formation of a competent and specific histone demethylase complex.