Serakinci Nedime, Hoare Stacey F, Kassem Moustapha, Atkinson Stuart P, Keith W Nicol
University of Southern Denmark, Institute of Medical Biology, Department of Anatomy and Neurobiology, Odense C, Denmark.
Regen Med. 2006 Jan;1(1):125-31. doi: 10.2217/17460751.1.1.125.
The human adult mesenchymal stem cell (hMSC) does not express telomerase and has been shown to be the target for neoplastic transformation after transduction with hTERT. These findings lend support to the stem cell hypothesis of cancer development but by supplying hTERT, the molecular events required to upregulate hTERT expression in cancer development are missed. Therefore, the hMSC is ideal for the identification of molecular mechanisms regulating telomerase gene expression in stem cells. This study shows that the repression of hTERT expression in hMSC is chromatin based and that modifications of the chromatin environment lead to reactivation of telomerase gene expression. It is shown that repression of hTERT expression in hMSCs is due to promoter-specific histone hypoacetylation coupled with low Pol II and TFIIB trafficking. This repression is overcome by treatment with Trichostatin A (TSA), an HDAC inhibitor, concomitant with increases in promoter-specific histone acetylation and increases in Pol II and TFIIB tracking. hTR expression is also increased in TSA-treated hMSCs, concomitant with changes in Pol II and TFIIB dynamics.
人类成人间充质干细胞（hMSC）不表达端粒酶，并且已被证明是用hTERT转导后发生肿瘤转化的靶点。这些发现支持了癌症发展的干细胞假说，但通过提供hTERT，却遗漏了癌症发展过程中上调hTERT表达所需的分子事件。因此，hMSC是鉴定调节干细胞中端粒酶基因表达的分子机制的理想选择。本研究表明，hMSC中hTERT表达的抑制是基于染色质的，并且染色质环境的改变导致端粒酶基因表达的重新激活。结果表明，hMSC中hTERT表达的抑制是由于启动子特异性组蛋白低乙酰化以及低水平的Pol II和TFIIB转运。用组蛋白去乙酰化酶（HDAC）抑制剂曲古抑菌素A（TSA）处理可克服这种抑制，同时启动子特异性组蛋白乙酰化增加，Pol II和TFIIB的跟踪增加。在TSA处理的hMSC中，hTR表达也增加，同时伴有Pol II和TFIIB动力学的变化。
