H3K4me3 inversely correlates with DNA methylation at a large class of non-CpG-island-containing start sites.
H3K4me3 inversely correlates with DNA methylation at a large class of non-CpG-island-containing start sites.
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DOI：
10.1186/gm346
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发表时间：
2012-05-28
期刊：
影响因子：
12.3
通讯作者：
Scacheri PC
中科院分区：
文献类型：
--
作者：
Balasubramanian D;Akhtar-Zaidi B;Song L;Bartels CF;Veigl M;Beard L;Myeroff L;Guda K;Lutterbaugh J;Willis J;Crawford GE;Markowitz SD;Scacheri PC
除了突变之外，基因的表观遗传沉默已被认为是促进人类致癌的基本机制。迄今为止，表观遗传基因沉默的表征主要集中在基因沉默介导的启动子相关的CpG岛的超甲基化，与H3 K4 me 3染色质标记的损失。对缺少CpG岛的启动子或被替代机制抑制的基因知之甚少。我们在结肠癌细胞和正常结肠粘膜中进行了整合ChIP芯片、DNase-seq和全局基因表达分析，以表征结肠癌中经历沉默的基因的富含CpG和缺乏CpG的启动子的染色质特征。基于H3 K4 me 3在转录起始位点的保留或丢失，结肠癌中的表观遗传学抑制基因分为两类。在结肠癌中丢失H3 K4 me 3的转录抑制基因（K4依赖性基因）中，很大一部分实际上缺乏CpG岛。然而，类似于含有CpG岛的基因，位于K4依赖性基因起始位点附近的胞嘧啶变成DNA高甲基化，并且被抑制的K4依赖性基因可以用5-氮杂胞苷重新激活。此外，我们还表明，当保留H3 K4 me 3标记时，CpG岛相关基因的沉默可以通过另一种机制进行，其中抑制性染色质标记被招募。H3 K4 me 3在结肠癌中的CpG岛和非CpG岛起始位点处同等地保护免于DNA甲基化。此外，研究结果表明，CpG丰富的基因抑制的损失H3 K4 me 3和DNA甲基化的一个更一般的表观遗传机制的基因沉默，其中一个基因沉默介导的损失H3 K4 me 3和甲基化的非CpG岛启动子相关的胞嘧啶的特殊情况。
In addition to mutations, epigenetic silencing of genes has been recognized as a fundamental mechanism that promotes human carcinogenesis. To date, characterization of epigenetic gene silencing has largely focused on genes in which silencing is mediated by hypermethylation of promoter-associated CpG islands, associated with loss of the H3K4me3 chromatin mark. Far less is known about promoters lacking CpG-islands or genes that are repressed by alternative mechanisms. We performed integrative ChIP-chip, DNase-seq, and global gene expression analyses in colon cancer cells and normal colon mucosa to characterize chromatin features of both CpG-rich and CpG-poor promoters of genes that undergo silencing in colon cancer. Epigenetically repressed genes in colon cancer separate into two classes based on retention or loss of H3K4me3 at transcription start sites. Quantitatively, of transcriptionally repressed genes that lose H3K4me3 in colon cancer (K4-dependent genes), a large fraction actually lacks CpG islands. Nonetheless, similar to CpG-island containing genes, cytosines located near the start sites of K4-dependent genes become DNA hypermethylated, and repressed K4-dependent genes can be reactivated with 5-azacytidine. Moreover, we also show that when the H3K4me3 mark is retained, silencing of CpG island-associated genes can proceed through an alternative mechanism in which repressive chromatin marks are recruited. H3K4me3 equally protects from DNA methylation at both CpG-island and non-CpG island start sites in colon cancer. Moreover, the results suggest that CpG-rich genes repressed by loss of H3K4me3 and DNA methylation represent special instances of a more general epigenetic mechanism of gene silencing, one in which gene silencing is mediated by loss of H3K4me3 and methylation of non-CpG island promoter-associated cytosines.
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影响因子：
64.5
作者：
Guenther, Matthew G.;Levine, Stuart S.;Young, Richard A.
通讯作者：
Young, Richard A.
影响因子：
7
作者：
Li, Heng;Ruan, Jue;Durbin, Richard
通讯作者：
Durbin, Richard
影响因子：
30.8
作者：
Weber, Michael;Hellmann, Ines;Schubeler, Dirk
通讯作者：
Schubeler, Dirk
影响因子：
64.5
作者：
Bernstein, BE;Mikkelsen, TS;Lander, ES
通讯作者：
Lander, ES
影响因子：
12.3
作者：
Schug J;Schuller WP;Kappen C;Salbaum JM;Bucan M;Stoeckert CJ Jr
通讯作者：
Stoeckert CJ Jr