Gene silencing of MIR22 in acute lymphoblastic leukaemia involves histone modifications independent of promoter DNA methylation
Gene silencing of MIR22 in acute lymphoblastic leukaemia involves histone modifications independent of promoter DNA methylation
复制标题
急性淋巴细胞白血病中 MIR22 的基因沉默涉及独立于启动子 DNA 甲基化的组蛋白修饰
DOI：
10.1111/j.1365-2141.2009.07920.x
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发表时间：
2010-01-01
影响因子：
6.5
通讯作者：
Chen, Xian-Ming
中科院分区：
文献类型：
--
作者：
Li, Xiaoqing;Liu, Jun;Chen, Xian-Ming
异常的表观遗传调控最近被认为与肿瘤抑制因子microRNAs(MiRNAs)的下调有关。组蛋白修饰和DNA甲基化可以在癌症的基因沉默中发挥不同的作用。为探讨组蛋白修饰是否导致急性淋巴细胞白血病(ALL)中miRNAs的异常表达，应用基因芯片技术分析了组蛋白去乙酰化酶抑制剂曲古抑素A(TSA)对B细胞前体细胞株NALM-6的miRNA表达谱的影响。在TSA上调的miRNAs中，miR22是一种外显子miRNA，位于非编码转录本MGC14376的第二外显子。经TSA处理后，NALM-6细胞和原代人ALL肿瘤细胞miR22转录均上调。虽然在miR22的启动子元件中发现了一个CpG岛，但在这些细胞中没有检测到启动子DNA甲基化。相反，组蛋白抑制标记H3K27三甲基化(H3K27triM)在基因转录起始点附近发现积累，TSA处理减少了该基因的转录起始点。因此，H3K27triM的积累不依赖于启动子DNA甲基化，可能是ALL中miR22沉默的一种新的表观遗传学机制。
Aberrant epigenetic regulation has recently been implicated in the downregulation of tumour suppressor microRNAs (miRNAs). Histone modification and DNA methylation can have different roles in gene silencing in cancer. To investigate whether histone modifications would contribute to the dysregulation of miRNAs in acute lymphoblastic leukaemia (ALL), the effect of a histone deacetylase inhibitor, trichostatin A (TSA), on miRNA expression profile was analysed by microarray assay in a precursor B‐cell ALL cell line NALM‐6. A total of 10 miRNAs were downregulated and 31 were upregulated significantly following TSA treatment. Among TSA‐upregulated miRNAs, MIR22 is an extronic miRNA and resides in the second exon of the non‐coding transcript MGC14376. Upregulation of MIR22 transcription was found in both NALM‐6 cells and primary human ALL malignant cells treated with TSA. Whereas a CpG island was identified within the promoter element of MIR22, no promoter DNA methylation was detected in these cells. In contrast, accumulation of the repressive histone marker H3K27 trimethylation (H3K27triM) was indentified around the transcriptional start point of the gene, which was reduced by TSA treatment. Thus, accumulation of H3K27triM independent of promoter DNA methylation may be a novel epigenetic mechanism for MIR22 silencing in ALL.