Epigenetic silencing of Bim transcription by Spi-1/PU.1 promotes apoptosis resistance in leukaemia
Epigenetic silencing of Bim transcription by Spi-1/PU.1 promotes apoptosis resistance in leukaemia
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DOI：
10.1038/cdd.2013.88
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发表时间：
2013-09-01
影响因子：
12.4
通讯作者：
Guillouf, C.
中科院分区：
文献类型：
--
作者：
Ridinger-Saison, M.;Evanno, E.;Guillouf, C.
转录网络的失调会导致造血系统恶性肿瘤。转录因子 Spi-1/PU.1 是造血的主要调节因子，其改变会导致白血病。 Spi-1 过表达可抑制红白血病细胞的分化并促进细胞凋亡的抵抗。在这里，我们证明 Spi-1 通过促凋亡因子 Bim 的转录抑制在体外和体内抑制线粒体凋亡。 BIM 与 MCL-1 相互作用，MCL-1 在白血病前期细胞的存活中起主要作用。 BIM 表达的抑制减少了 BIM-MCL-1 复合物的数量，从而增加了潜在活性抗凋亡 MCL-1 的比例。然后，我们证明 Spi-1 通过与 Bim 启动子结合并促进 Bim 启动子上赖氨酸 27（H3K27me3，抑制性组蛋白标记）上组蛋白 3 的三甲基化来抑制 Bim 转录。 Polycomb 的 PRC2 抑制复合体直接负责 H3K27me3 标记在 Bim 启动子上的沉积。 SUZ12 和组蛋白甲基转移酶 EZH2 这两个 PRC2 亚基与 Bim 启动子的结合位置与 H3K27me3 相同，与 Spi-1 DNA 结合位点不同。由于 Spi-1 与 SUZ12 和 EZH2 相互作用，这些结果表明 Spi-1 调节 PRC2 的活性，而不直接将复合物募集到其在染色质上的活性位点。我们的结果确定了 Spi-1 抑制转录的新机制，并为基因表达的表观遗传控制介导的转录因子的抗凋亡功能提供了机制见解。
Deregulation of transcriptional networks contributes to haematopoietic malignancies. The transcription factor Spi-1/PU.1 is a master regulator of haematopoiesis and its alteration leads to leukaemia. Spi-1 overexpression inhibits differentiation and promotes resistance to apoptosis in erythroleukaemia. Here, we show that Spi-1 inhibits mitochondrial apoptosis in vitro and in vivo through the transcriptional repression of Bim, a proapoptotic factor. BIM interacts with MCL-1 that behaves as a major player in the survival of the preleukaemic cells. The repression of BIM expression reduces the amount of BIM-MCL-1 complexes, thus increasing the fraction of potentially active antiapoptotic MCL-1. We then demonstrate that Spi-1 represses Bim transcription by binding to the Bim promoter and by promoting the trimethylation of histone 3 on lysine 27 (H3K27me3, a repressive histone mark) on the Bim promoter. The PRC2 repressive complex of Polycomb is directly responsible for the deposit of H3K27me3 mark at the Bim promoter. SUZ12 and the histone methyltransferase EZH2, two PRC2 subunits bind to the Bim promoter at the same location than H3K27me3, distinct of the Spi-1 DNA binding site. As Spi-1 interacts with SUZ12 and EZH2, these results indicate that Spi-1 modulates the activity of PRC2 without directly recruiting the complex to the site of its activity on the chromatin. Our results identify a new mechanism whereby Spi-1 represses transcription and provide mechanistic insights on the antiapoptotic function of a transcription factor mediated by the epigenetic control of gene expression.