Lack of telomerase gene expression in alternative lengthening of telomere cells is associated with chromatin remodeling of the hTR and hTERT gene promoters
Lack of telomerase gene expression in alternative lengthening of telomere cells is associated with chromatin remodeling of the hTR and hTERT gene promoters
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DOI：
10.1158/0008-5472.can-05-1715
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发表时间：
2005-09-01
期刊：
影响因子：
11.2
通讯作者：
Keith, WN
中科院分区：
文献类型：
--
作者：
Atkinson, SP;Hoare, SF;Keith, WN
在不朽细胞中存在活跃的端粒维持机制，可以通过维持端粒长度来绕过衰老。在大多数不朽的细胞系和肿瘤中，端粒的维持可归因于端粒酶的再激活。然而，一些不朽的细胞系和肿瘤可以在端粒酶活性缺失的情况下通过选择性延长端粒（ALT）机制实现端粒维持。表观遗传机制与端粒酶表达的调控有关。我们发现，在ALT、正常和端粒酶阳性肿瘤细胞系中，染色质环境中hTR和hTERT启动子的特异性修饰与hTR和hTERT的表达相关。ALT细胞系hTR和hTERT缺乏表达与组蛋白H3和H4的低乙酰化和Lys(9)组蛋白H3的甲基化有关。相反，在端粒酶阳性细胞系中，hTR和hTERT的表达与H3和H4的超乙酰化以及Lys(4) H3的甲基化有关。Lys(20) H4的甲基化与基因表达无关，而是针对ALT细胞的hTR和hTERT启动子。这可能为ALT和端粒酶阳性细胞之间的差异以及ALT表型的新标记提供了见解。5-azadeoxycytidine联合曲古抑素A处理正常和ALT细胞，可引起ALT和正常细胞系启动子的染色质重塑和hTR和hTERT表达的再激活。这些数据在端粒酶基因启动子的染色质环境和转录活性之间建立了明确的联系。
The presence of active telomere maintenance mechanisms in immortal cells allows the bypass of senescence by maintaining telomere length. In most immortal cell lines and tumors, telomere maintenance is attributable to telomerase reactivation. However, a number of immortal cell lines and tumors can achieve telomere maintenance in the absence of detectable telomerase activity by the alternative lengthening of telomere (ALT) mechanism. Epigenetic mechanisms have been implicated in the regulation of telomerase expression. We show that specific modifications within the chromatin environment of the hTR and hTERT promoters correlate with expression of hTR and hTERT in ALT, normal and telomerasepositive tumor cell lines. Lack of expression of hTR and hTERT in ALT cell lines is associated with histone H3 and H4 hypoacetylation and methylation of Lys(9) histone H3. Conversely, hTR and hTERT expression in telomerase-positive cell lines is associated with hyperacetylation of H3 and H4 and methylation of Lys(4) H3. Methylation of Lys(20) H4 was not linked to gene expression but instead was specific to the hTR and hTERT promoters of ALT cells. This may provide an insight into the differences between ALT and telomerase-positive cells as well as a novel marker for the ALT phenotype. Treatment of normal and ALT cells with 5-azadeoxycytidine in combination with Trichostatin A caused chromatin remodeling of both promoters and reactivation of hTR and hTERT expression in ALT and normal cell lines. This data establishes a definite link between the chromatin environment of the telomerase gene promoters and transcriptional activity.