Allelic silencing at the tumor-suppressor locus 13q14.3 suggests an epigenetic tumor-suppressor mechanism
Allelic silencing at the tumor-suppressor locus 13q14.3 suggests an epigenetic tumor-suppressor mechanism
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DOI：
10.1073/pnas.0600494103
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发表时间：
2006-05-16
影响因子：
11.1
通讯作者：
Lichter, Peter
中科院分区：
文献类型：
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作者：
Mertens, Daniel;Wolf, Stephan;Lichter, Peter
来自视网膜母细胞瘤位点远端的染色体带13q14.3的基因组物质在多种人类肿瘤中反复丢失，这表明一种尚未确定的肿瘤抑制机制。到目前为止，在最小缺失区域未发现致病性突变。然而，在失去一个关键区域拷贝的B细胞慢性淋巴细胞白血病肿瘤中，各自的候选肿瘤抑制基因被一个因子>2下调，这是正常基因剂量效应所期望的。这一发现指向一种表观遗传病理机制。我们发现关键区域的两个拷贝不同步复制，这表明13q14.3的两个拷贝的染色质包装存在差异。虽然我们也发现了位于关键区域的基因的单等位基因沉默，但单等位基因的表达来自母亲或父亲的拷贝，不包括印迹机制。DNA甲基化分析显示该区域的一个CpG岛被甲基化。CpG岛的DNA去甲基化和全局组蛋白超乙酰化诱导双等位基因表达，而复制时间不受影响。我们认为，差异复制时间代表了区分13q14.3两个拷贝的早期表观遗传标记，导致差异染色质包装和单等位基因表达。因此，13q14.3单个活性拷贝的缺失导致候选基因的显著下调和功能丧失，为B细胞慢性淋巴细胞白血病中13q14.3基因病变和表观遗传沉默的相互作用提供了模型。
Genomic material from chromosome band 13q14.3 distal to the retinoblastoma locus is recurrently lost in a variety of human neoplasms, indicating an as-yet-unidentified tumor-suppressor mechanism. No pathogenic mutations have been found in the minimally deleted region until now. However, in B cell chronic lymphocytic leukemia tumors with loss of one copy of the critical region, respective candidate tumor-suppressor genes are down-regulated by a factor > 2, which would be expected by a normal gene-dosage effect. This finding points to an epigenetic pathomechanism. We find that the two copies of the critical region replicate asynchronously, suggesting differential chromatin packaging of the two copies of 13q14.3. Although we also detect monoallelic silencing of genes localized in the critical region, monoallelic expression originates from either the maternal or paternal copy, excluding an imprinting mechanism. DNA methylation analyses revealed one CpG island of the region to be methylated. DNA demethylation of this CpG island and global histone hyperacetylation induced biallelic expression, whereas replication timing was not affected. We propose that differential replication timing represents an early epigenetic mark that distinguishes the two copies of 13q14.3, resulting in differential chromatin packaging and monoallelic expression. Accordingly, deletion of the single active copy of 13q14.3 results in significant downregulation of the candidate genes and loss of function, providing a model for the interaction of genetic lesions and epigenetic silencing at 13q14.3 in B cell chronic lymphocytic leukemia.