白血病中 H3K9 甲基转移酶 G9a 对 JAK2 的负调控。
Negative regulation of JAK2 by H3K9 methyltransferase G9a in leukemia.
机构信息
Department of Life Science, College of Natural Sciences, Research Center for Biomolecules and Biophysics, Chung-Ang University, Seoul, Republic of Korea.
出版信息
Mol Cell Biol. 2012 Sep;32(18):3681-94. doi: 10.1128/MCB.00673-12. Epub 2012 Jul 16.
Abstract
Histone methylation at specific lysine residues is a crucial regulatory process in transcriptional regulation. Using chromatin immunoprecipitation with microarray technology (ChIP-chip) analysis, we found that the H3K9-me2 target gene JAK2 was an important factor during differentiation of the HL-60 promyelocytic leukemia cell line by all-trans-retinoic acid (ATRA) treatment. Here, we report that the H3K9 methyltransferase G9a negatively regulated JAK2 transcription in histone methyltransferase activity and in a YY1-dependent manner during ATRA-mediated leukemia cell differentiation. We found that G9a knockdown repressed ATRA-mediated HL-60 cell differentiation. We demonstrated that G9a interacts with YY1 and is recruited to the JAK2 promoter along with corepressors, including histone deacetylase, that induced H3K9-me2. Repression of JAK2 transcription by G9a decreased H3Y41 phosphorylation and promoted inhibition of the recently identified JAK2-H3Y41P-HP1α pathway-mediated leukemogenesis.
摘要
组蛋白在特定赖氨酸残基上的甲基化是转录调控中一个重要的调节过程。使用染色质免疫沉淀与微阵列技术（ChIP-chip）分析，我们发现 H3K9-me2 的靶基因 JAK2 是全反式维甲酸（ATRA）处理诱导 HL-60 早幼粒细胞白血病细胞系分化过程中的一个重要因素。在这里，我们报告 H3K9 甲基转移酶 G9a 通过组蛋白甲基转移酶活性和在 ATRA 介导的白血病细胞分化中依赖于 YY1 的方式负调控 JAK2 转录。我们发现 G9a 的敲低抑制了 ATRA 介导的 HL-60 细胞分化。我们证明 G9a 与 YY1 相互作用，并与包括组蛋白去乙酰化酶在内的共抑制子一起被招募到 JAK2 启动子上，诱导 H3K9-me2。G9a 对 JAK2 转录的抑制降低了 H3Y41 的磷酸化，并促进了最近发现的 JAK2-H3Y41P-HP1α 通路介导的白血病发生的抑制。
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