SCFFBXO22 Regulates Histone H3 Lysine 9 and 36 Methylation Levels by Targeting Histone Demethylase KDM4A for Ubiquitin-Mediated Proteasomal Degradation
SCFFBXO22 Regulates Histone H3 Lysine 9 and 36 Methylation Levels by Targeting Histone Demethylase KDM4A for Ubiquitin-Mediated Proteasomal Degradation
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DOI：
10.1128/mcb.05746-11
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发表时间：
2011-09-01
影响因子：
5.3
通讯作者：
Harper, J. Wade
中科院分区：
文献类型：
--
作者：
Tan, Meng-Kwang Marcus;Lim, Hui-Jun;Harper, J. Wade
赖氨酸残基的可逆甲基化已成为表观遗传调控的中心机制，也是“组蛋白密码”的一个组成部分，组蛋白密码产生带有基因调控信息的组蛋白。KDM4A是一种组蛋白去甲基酶，针对组蛋白H3赖氨酸9和36上的三甲基化和二甲基化标记。虽然KDM4A的丰度在细胞周期中振荡，但人们对该酶如何调节以实现对染色质中特定组蛋白残基的靶向作用知之甚少。在这里，我们报告了一个以前没有研究过的SCFFBXO22泛素连接酶复合体，通过靶向蛋白酶体的转换来控制KDM4A的活性。FBXO22通过其胞内信号转导(FIST)结构域识别KDM4A的催化JmjN/JmjC结构域，从而发挥KDM4A的受体作用。RNA干扰或过表达对FBXO22水平的调节分别导致KDM4A水平的升高或降低。KDM4A丰度的变化与组蛋白H3赖氨酸9和36甲基化水平的变化以及KDM4A靶基因ASCL2的转录相关。综上所述，这些结果表明，SCFFBXO22通过控制KDM4A水平来调节组蛋白H3标记和同源转录调控途径的变化，并表明FBXO22可能通过控制KDM4A活性而在发育、分化和疾病中发挥潜在作用。
Reversible methylation of lysine residues has emerged as a central mechanism for epigenetic regulation and is a component of the "histone code," which engenders histones with gene regulatory information. KDM4A is a histone demethylase that targets tri- and dimethylation marks on histone H3 lysines 9 and 36. While the abundance of KDM4A oscillates in the cell cycle, little is known how this enzyme is regulated to achieve targeted effects on specific histone residues in chromatin. Here, we report that a previously unstudied SCFFBXO22 ubiquitin ligase complex controls the activity of KDM4A by targeting it for proteasomal turnover. FBXO22 functions as a receptor for KDM4A by recognizing its catalytic JmjN/JmjC domains via its intracellular signal transduction (FIST) domain. Modulation of FBXO22 levels by RNA interference or overexpression leads to increased or decreased levels of KDM4A, respectively. Changes in KDM4A abundance correlate with alterations in histone H3 lysine 9 and 36 methylation levels, and transcription of a KDM4A target gene, ASCL2. Taken together, these results demonstrate that SCFFBXO22 regulates changes in histone H3 marks and cognate transcriptional control pathways by controlling KDM4A levels, and they suggest a potential role for FBXO22 in development, differentiation, and disease through spatial and temporal control of KDM4A activity.