A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing
A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing
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DOI：
10.1038/ng1972
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发表时间：
2007-02-01
期刊：
影响因子：
30.8
通讯作者：
Baylin, Stephen B.
中科院分区：
文献类型：
--
作者：
Ohm, Joyce E.;McGarvey, Kelly M.;Baylin, Stephen B.
成人癌症可能起源于干细胞或早期祖细胞（1,2）。基因表达的表观遗传调控对于这些早期细胞的正常功能至关重要，但在癌症中却高度异常，通常表现为异常的启动子CpG岛超甲基化和肿瘤抑制基因和促分化因子的转录沉默（3-5）。我们发现，对于这些基因，正常和恶性胚胎细胞通常缺乏在成人癌症中发现的DNA高甲基化。在胚胎干细胞中，这些基因处于“转录就绪”状态，由“二价”启动子染色质模式介导，该模式包括抑制标记，组蛋白H3在Lys27 （H3K27）被Polycomb组蛋白甲基化，加上活性标记，甲基化H3K4。然而，胚胎癌细胞增加了两个关键的抑制标记，二甲基化H3K9和三甲基化H3K9，两者都与成人癌症的DNA超甲基化有关（6-8）。我们假设细胞染色质模式和干细胞或祖细胞中这些重要调控基因的短暂沉默可能使这些基因在肿瘤发生和发展过程中容易受到异常DNA超甲基化和遗传性基因沉默的影响。
Adult cancers may derive from stem or early progenitor cells(1,2). Epigenetic modulation of gene expression is essential for normal function of these early cells but is highly abnormal in cancers, which often show aberrant promoter CpG island hypermethylation and transcriptional silencing of tumor suppressor genes and pro-differentiation factors(3-5). We find that for such genes, both normal and malignant embryonic cells generally lack the hypermethylation of DNA found in adult cancers. In embryonic stem cells, these genes are held in a 'transcription- ready' state mediated by a 'bivalent' promoter chromatin pattern consisting of the repressive mark, histone H3 methylated at Lys27 ( H3K27) by Polycomb group proteins, plus the active mark, methylated H3K4. However, embryonic carcinoma cells add two key repressive marks, dimethylated H3K9 and trimethylated H3K9, both associated with DNA hypermethylation in adult cancers(6-8). We hypothesize that cell chromatin patterns and transient silencing of these important regulatory genes in stem or progenitor cells may leave these genes vulnerable to aberrant DNA hypermethylation and heritable gene silencing during tumor initiation and progression.