HP1 maintains protein stability of H3K9 methyltransferases and demethylases
HP1 maintains protein stability of H3K9 methyltransferases and demethylases
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DOI：
10.15252/embr.202153581
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发表时间：
2022-02-15
期刊：
影响因子：
7.7
通讯作者：
Tachibana, Makoto
中科院分区：
文献类型：
--
作者：
Maeda, Ryo;Tachibana, Makoto
H3K9(H3K9me2/3)是异染色质的表观遗传标记。异染色质蛋白1(HP1)特异性识别H3K9me2/3，有助于H3K9me2/3的转录抑制和传播。在这里，我们证明了HP1在异染色质组织中的另一个作用：调节H3K9甲基转移酶(H3K9 MTS)和去甲基酶(H3K9 DM)的蛋白质稳定性。我们发现H3K9 MTS的HP1相互作用缺陷突变体SUV39H1和SetDB1经历了蛋白质降解。我们进一步建立了缺乏所有三个HP1同源基因的小鼠胚胎干细胞系。在HP1缺失的细胞中，SUV39H1、Suv39h2、SetDB1和G9a/GLP复合体在蛋白质水平上减少，这些酶从染色质中释放出来。不能识别H3K9me2/3或形成二聚体的HP1突变体不能稳定这些酶，这表明H3K9 MT与染色质的结合对它们的蛋白质稳定性至关重要。我们发现HP1还稳定了H3K9 DM、Jmjd1a和Jmjd1b。我们的研究表明，哺乳动物HP1形成了一个异染色质中心，控制着H3K9 MT和H3K9 DM的蛋白质稳定性。
Di- or tri-methylated H3K9 (H3K9me2/3) is an epigenetic mark of heterochromatin. Heterochromatin protein 1 (HP1) specifically recognizes H3K9me2/3, contributing to transcriptional suppression and spread of H3K9me2/3. Here, we demonstrate another role of HP1 in heterochromatin organization: regulation of protein stability of H3K9 methyltransferases (H3K9 MTs) and demethylases (H3K9 DMs). We show that HP1 interaction-defective mutants of H3K9 MTs, Suv39h1 and Setdb1, undergo protein degradation. We further establish mouse embryonic stem cell lines lacking all three HP1 paralogs. In the HP1-deficient cells, Suv39h1, Suv39h2, Setdb1, and G9a/GLP complex decrease at the protein level, and the enzymes are released from chromatin. HP1 mutants that cannot recognize H3K9me2/3 or form dimers cannot stabilize these enzymes, indicating that the tethering of H3K9 MTs to chromatin is critical for their protein stability. We show that HP1 also stabilizes H3K9 DMs, Jmjd1a and Jmjd1b. Our study indicates that mammalian HP1 forms a heterochromatin hub that governs protein stability of H3K9 MTs and H3K9 DMs.