Epigenetic regulation of human telomerase reverse transcriptase promoter activity during cellular differentiation
Epigenetic regulation of human telomerase reverse transcriptase promoter activity during cellular differentiation
复制标题
DOI：
10.1002/gcc.20058
复制
发表时间：
2004-09-01
影响因子：
3.7
通讯作者：
Tollefsbol, TO
中科院分区：
文献类型：
--
作者：
Liu, L;Saldanha, SN;Tollefsbol, TO
人端粒酶逆转录酶（TERT）基因在大多数分化细胞中转录失活，但在大多数癌细胞中重新激活。为了阐明TERT在分化过程中是如何失活的，我们应用全反式维甲酸（ATRA）诱导人畸胎癌（HT）细胞和人急性髓性白血病（HL 60）细胞分化。我们首先发现，在ATRA诱导后，TERT启动子活性迅速下降，这先于内源性端粒酶活性的逐渐丧失。为了阐明分化过程中降低的TERT启动子活性的潜在机制，我们对TERT启动子进行了表观遗传学研究，发现了一个渐进的组蛋白低乙酰化，伴随着TERT启动子中甲基化胞嘧啶的逐渐积累。我们还观察到，在整个12天的分化过程中，多能HT细胞中的TERT启动子甲基化程度低于多能HL 60细胞。这种起源依赖性表观遗传变化也在组蛋白乙酰化研究中得到证实，表明TERT启动子在HT细胞中比在HL 60细胞中对脱乙酰化更具抗性。两者合计，我们的研究结果表明，协同参与的DNA甲基化和组蛋白去乙酰化的下调可能依赖于细胞类型的起源的端粒酶启动子活性，他们增加了新的见解端粒酶活性的方式可能在分化过程中进行调节。(C)2004 Wiley-Liss，Inc.
The human telomerase reverse transcriptase (TERT) gene is transcriptionally inactivated in most differentiated cells but is reactivated in the majority of cancer cells. To elucidate how TERT is inactivated during differentiation, we applied all-trans retinoic acid (ATRA) to induce the differentiation of human teratocarcinoma (HT) cells and human acute myeloid leukemia (HL60) cells. We first showed that TERT promoter activity decreased rapidly, which preceded a gradual loss of endogenous telomerase activity following ATRA induction. To elucidate the underlying mechanisms of the reduced TERT promoter activity during differentiation, we per-formed epigenetic studies on the TERT promoter and found a progressive histone hypoacetylation coupled with a gradual accumulation of methylated cytosines in the TERT promoter. We also observed that the TERT promoter was less methylated in pluripotent HT cells than in multipotent HL60 cells throughout a 12-day differentiation process. This origin-dependent epigenetic change was also confirmed in histone acetylation studies, indicating that the TERT promoter was more resistant to deacetylation in HT cells than in HL60 cells. Taken together, our results demonstrate synergistic involvement of DNA methylation and histone deacetylation in the down-regulation of TERT promoter activity that may be dependent on the origin of the cell types, and they add new insight into the way telomerase activity may be regulated during differentiation. (C) 2004 Wiley-Liss, Inc.