Serakinci Nedime, Mega Tiber Pınar, Orun Oya
Near East University, Medical Faculty, Department of Medical Genetics, Lefkosa, Mersin 10, Turkey; Near East University, Art and Sciences Faculty, Department of Molecular Biology and Genetics, Lefkosa, Mersin 10, Turkey Lefkosa, Mersin 10, Turkey; Telomere Aging Group, Center for IRS, Southern Denmark University, 7100 Vejle, Denmark.
Marmara University, School of Medicine, Biophysics Department, Istanbul, Turkey.
Eur J Med Genet. 2018 May;61(5):288-293. doi: 10.1016/j.ejmg.2017.12.014. Epub 2017 Dec 27.
Regulation of telomerase activity is thought to participate in the cellular response to ionizing radiation. Epigenetic mechanisms play a role in this regulation, as well as other mechanisms such as transcription, phosphorylation, etc. Here, we investigated chromatin modifications in telomerase promoter upon exposure to ionizing radiation in human mesenchymal stem cells (hMSC) and telomerase-immortalized hMSCs (hMSC-telo1) together with a hMSC-telo1 cell line in which TRF2 expression was partially repressed (siTRF2 hMSC-telo1). Histone methylations and acetylations were compared in all cell lines after exposure to various doses of ionizing radiation (0.1, 1, 2.5 and 15 Gy) using chromatin immunoprecipitation assay. hTERT gene was shown to be quickly regulated through H3, H4 acetylations, as well as with H3K4 and H3K9 methylations, following radiation exposure, although the kinetic of hMSC-telo1 cells were different, indicative of the higher radioresistivity of these cells. To the author's surprise, there was an upregulation of endogenous telomerase activity in the hMSC-telo1 cells, even though the cells had already expressed high levels of ectopic hTERT. Our results show that telomerase regulation is one of the primary actions in response to damage and epigenetic factors play a major role in this regulation. Our results also suggested that partial silencing of TRF2 enhances the radiosensitivity of these cells, and endogenous telomerase is upregulated upon radiation, even under ectopic expression of hTERT in these cells.
端粒酶活性的调控被认为参与了细胞对电离辐射的反应。表观遗传机制以及转录、磷酸化等其他机制在这种调控中发挥作用。在此，我们研究了人骨髓间充质干细胞（hMSC）、端粒酶永生化的hMSC（hMSC-telo1）以及TRF2表达部分受到抑制的hMSC-telo1细胞系（siTRF2 hMSC-telo1）在暴露于电离辐射后端粒酶启动子的染色质修饰。使用染色质免疫沉淀分析比较了所有细胞系在暴露于不同剂量电离辐射（0.1、1、2.5和15 Gy）后的组蛋白甲基化和乙酰化情况。结果显示，辐射暴露后，hTERT基因通过H3、H4乙酰化以及H3K4和H3K9甲基化被快速调控，尽管hMSC-telo1细胞的动力学不同，这表明这些细胞具有更高的放射抗性。令作者惊讶的是，hMSC-telo1细胞中内源性端粒酶活性上调，尽管这些细胞已经表达了高水平的异位hTERT。我们的结果表明，端粒酶调控是细胞对损伤反应的主要作用之一，表观遗传因素在这种调控中起主要作用。我们的结果还表明，TRF2的部分沉默增强了这些细胞的放射敏感性，并且即使在这些细胞中异位表达hTERT的情况下，辐射后内源性端粒酶也会上调。
