Role of hMOF-dependent histone H4 lysine 16 acetylation in the maintenance of TMS1/ASC gene activity.
Role of hMOF-dependent histone H4 lysine 16 acetylation in the maintenance of TMS1/ASC gene activity.
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DOI：
10.1158/0008-5472.can-08-0141
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发表时间：
2008-08-15
期刊：
影响因子：
11.2
通讯作者：
Vertino PM
中科院分区：
文献类型：
--
作者：
Kapoor-Vazirani P;Kagey JD;Powell DR;Vertino PM
人类肿瘤中肿瘤抑制基因的表观遗传沉默与启动子区CpG岛的异常甲基化和组蛋白修饰的局部改变有关。然而，驱动这些事件的机制仍不清楚。在这里，我们建立了一个重要的作用，组蛋白H4赖氨酸16乙酰化（H4 K16 Ac）和组蛋白乙酰转移酶hMOF在调节TMS 1/ASC，一个促凋亡基因，在人类癌症中经历表观遗传沉默。在未甲基化和活性状态下，TMS 1 CpG岛由定位的核小体跨越，并由组蛋白H3 K4甲基化标记。H4 K16 Ac独特地定位于两个尖锐的峰，其侧接未甲基化的CpG岛并且对应于强定位的核小体。TMS 1的异常甲基化和沉默伴随着H4 K16 Ac峰的丢失、核小体定位的丢失、H3 K4的低甲基化和H3 K9的高甲基化。此外，在转录起始位点附近观察到组蛋白H4赖氨酸20三甲基化的单峰。下调hMOF或MSL复合物的另一组分导致H4 K16 Ac的基因特异性降低、核小体定位的丧失和TMS 1的沉默。由H4 K16去乙酰化诱导的基因沉默独立于组蛋白甲基化和DNA甲基化的变化而发生，并且在hMOF重新表达时逆转。这些结果表明，选择性标记的CpG岛侧翼的hMOF是必需的TMS 1基因的活性，并建议，H4 K16 Ac的损失，核小体的动员和转录下调可能是重要的事件在某些肿瘤抑制基因的表观遗传沉默在癌症。
Epigenetic silencing of tumor suppressor genes in human cancers is associated with aberrant methylation of promoter region CpG islands and local alterations in histone modifications. However, the mechanisms that drive these events remain unclear. Here, we establish an important role for histone H4 lysine 16 acetylation (H4K16Ac) and the histone acetyltransferase hMOF in the regulation of TMS1/ASC, a proapoptotic gene that undergoes epigenetic silencing in human cancers. In the unmethylated and active state, the TMS1 CpG island is spanned by positioned nucleosomes and marked by histone H3K4 methylation. H4K16Ac was uniquely localized to two sharp peaks that flanked the unmethylated CpG island and corresponded to strongly positioned nucleosomes. Aberrant methylation and silencing of TMS1 was accompanied by loss of the H4K16Ac peaks, loss of nucleosome positioning, hypomethylation of H3K4 and hypermethylation of H3K9. In addition, a single peak of histone H4 lysine 20 trimethylation was observed near the transcription start site. Downregulation of hMOF or another component of the MSL complex resulted in a gene-specific decrease in H4K16Ac, loss of nucleosome positioning and silencing of TMS1. Gene silencing induced by H4K16 deacetylation occurred independently of changes in histone methylation and DNA methylation and was reversed upon hMOF re-expression. These results indicate that the selective marking of nucleosomes flanking the CpG island by hMOF is required to maintain TMS1 gene activity, and suggest that the loss of H4K16Ac, mobilization of nucleosomes and transcriptional downregulation may be important events in the epigenetic silencing of certain tumor suppressor genes in cancer.