Miousse Isabelle R, Chang Jianhui, Shao Lijian, Pathak Rupak, Nzabarushimana Étienne, Kutanzi Kristy R, Landes Reid D, Tackett Alan J, Hauer-Jensen Martin, Zhou Daohong, Koturbash Igor
Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Department of Pharmaceutical Sciences, Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Int J Mol Sci. 2017 Jul 4;18(7):1430. doi: 10.3390/ijms18071430.
Long Interspersed Nuclear Element 1 (LINE-1) retrotransposons are the major repetitive elements in mammalian genomes. LINE-1s are well-accepted as driving forces of evolution and critical regulators of the expression of genetic information. Alterations in LINE-1 DNA methylation may lead to its aberrant activity and are reported in virtually all human cancers and in experimental carcinogenesis. In this study, we investigated the endogenous DNA methylation status of the 5' untranslated region (UTR) of LINE-1 elements in the bone marrow hematopoietic stem cells (HSCs), hematopoietic progenitor cells (HPCs), and mononuclear cells (MNCs) in radioresistant C57BL/6J and radiosensitive CBA/J mice and in response to ionizing radiation (IR). We demonstrated that basal levels of DNA methylation within the 5'-UTRs of LINE-1 elements did not differ significantly between the two mouse strains and were negatively correlated with the evolutionary age of LINE-1 elements. Meanwhile, the expression of LINE-1 elements was higher in CBA/J mice. At two months after irradiation to 0.1 or 1 Gy of Cs (dose rate 1.21 Gy/min), significant decreases in LINE-1 DNA methylation in HSCs were observed in prone to radiation-induced carcinogenesis CBA/J, but not C57BL/6J mice. At the same time, no residual DNA damage, increased ROS, or changes in the cell cycle were detected in HSCs of CBA/J mice. These results suggest that epigenetic alterations may potentially serve as driving forces of radiation-induced carcinogenesis; however, future studies are needed to demonstrate the direct link between the LINE-1 DNA hypomethylation and radiation carcinogenesis.
长散在核元件1（LINE-1）逆转录转座子是哺乳动物基因组中的主要重复元件。LINE-1被公认为是进化的驱动力和遗传信息表达的关键调节因子。LINE-1 DNA甲基化的改变可能导致其异常活性，几乎在所有人类癌症和实验性致癌过程中都有报道。在本研究中，我们调查了抗辐射的C57BL/6J小鼠和辐射敏感的CBA/J小鼠的骨髓造血干细胞（HSC）、造血祖细胞（HPC）和单核细胞（MNC）中LINE-1元件5'非翻译区（UTR）的内源性DNA甲基化状态，以及对电离辐射（IR）的反应。我们证明，LINE-1元件5'-UTR内的DNA甲基化基础水平在两种小鼠品系之间没有显著差异，并且与LINE-1元件的进化年龄呈负相关。同时，LINE-1元件在CBA/J小鼠中的表达更高。在接受0.1或1 Gy Cs照射（剂量率1.21 Gy/min）两个月后，在易发生辐射诱导致癌的CBA/J小鼠而非C57BL/6J小鼠中，观察到HSC中LINE-1 DNA甲基化显著降低。同时，在CBA/J小鼠的HSC中未检测到残留的DNA损伤、ROS增加或细胞周期变化。这些结果表明，表观遗传改变可能是辐射诱导致癌的潜在驱动力；然而，未来还需要研究来证明LINE-1 DNA低甲基化与辐射致癌之间的直接联系。
