Chromatin modifications induced by PML-RARα repress critical targets in leukemogenesis as analyzed by ChIP-Chip
Chromatin modifications induced by PML-RARα repress critical targets in leukemogenesis as analyzed by ChIP-Chip
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DOI：
10.1182/blood-2007-03-079921
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发表时间：
2008-03-01
期刊：
影响因子：
20.3
通讯作者：
Mueller-Tidow, Carsten
中科院分区：
文献类型：
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作者：
Hoemme, Claudia;Peerzada, Abdul;Mueller-Tidow, Carsten
易位t(15；17)产生嵌合的PML-RARα转录因子，它是急性早幼粒细胞白血病的起始事件。通过全基因组结合和染色质修饰分析，结合全基因组表达数据，获得了PML-RARα转录功能的全局视图。染色质免疫沉淀(CHIP)芯片实验确定了372个直接的基因组PML-RARα靶点。其中一个亚群在原发急性早幼粒细胞白血病中得到证实。直接PML-RARα。靶标包括全球转录计划的调节者，以及细胞周期控制和细胞凋亡等基本细胞功能的关键调控基因。PML-RARα结合普遍导致HDAC1聚集，组蛋白H3乙酰化丧失，组蛋白H3赖氨酸9三甲基化增加，组蛋白H3赖氨酸4三甲基化增加。PML-RARα与靶启动子结合并导致组蛋白修饰导致功能相关基因的mRNA抑制。综上所述，我们的结果表明，转录因子PML-RARα通过诱导其直接基因组靶基因上抑制的染色质形成来调节关键的癌症相关基因和途径。
The translocation t(15;17) generates the chimeric PML-RAR alpha transcription factor that is the initiating event of acute promyelocytic leukemia. A global view of PML-RAR alpha transcriptional functions was obtained by genome-wide binding and chromatin modification analyses combined with genome-wide expression data. Chromatin immunoprecipitation (ChIP)-chip experiments identified 372 direct genomic PML-RAR alpha targets. A subset of these was confirmed in primary acute promyelocytic leukemia. Direct PML-RAR alpha. targets include regulators of global transcriptional programs as well as critical regulatory genes for basic cellular functions such as cell-cycle control and apoptosis. PML-RAR alpha binding universally led to HDAC1 recruitment, loss of histone H3 acetylation, increased trimethylation of histone H3 lysine 9, and unexpectedly increased trimethylation of histone H3 lysine 4. The binding of PML-RAR alpha to target promoters and the result ing histone modifications resulted in mRNA repression of functionally relevant genes. Taken together, our results reveal that the transcription factor PML-RAR alpha regulates key cancer-related genes and pathways by inducing a repressed chromatin formation on its direct genomic target genes.