Inter-Strain Differences in LINE-1 DNA Methylation in the Mouse Hematopoietic System in Response to Exposure to Ionizing Radiation

Abstract

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 137Cs (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.

Accumulation of DNA methylation alterations in paediatric glioma stem cells following fractionated dose irradiation

“…We found that loci in long repetitive regions were significantly enhanced in DMPs following 15 and 15 + 3 FDIR, demonstrating that also irradiation can induce such alterations. This is in agreement with earlier studies showing decreased DNA methylation in repetitive elements with radiation in various models [47][48][49][50].…”

2017 Michael Fry Award Lecture When DNA is Actually Not a Target: Radiation Epigenetics as a Tool to Understand and Control Cellular Response to Ionizing Radiation

“…1). Importantly, this effect was organ-and cell-type independent as it was observed in the lung, intestine and the bone marrow, and in the cells of various lineages of the hematopoietic system (38, 39, 41). In general, the radiation-induced loss of DNA methylation was observed primarily from the evolutionary young LINE-1 elements that were enriched in methylated CGI sites.…”

“…Those differences could be explained by the different types of radiation and doses, models used, as well as different methods of DNA methylation analysis. However, we recently demonstrated that effects of radiation on LINE-1 DNA methylation are dependent primarily on the following two factors: the evolutionary age/type of the LINE-1 promoter and the type of irradiated cell (38, 39). …”

“…In contrast, older LINE-1 elements, with a number demethylated during the evolution CGI sites, were able to acquire additional methyl groups, leading to DNA hypermethylation in these loci. The DNA methylation status of the evolutionary-oldest elements remained often unchanged due to the initially hypomethylated phenotype on one hand and the loss of a substantial fraction of potential CGI sites due to spontaneous deamination on the other hand (38, 39). …”

“…The most pronounced responses were detected in hematopoietic stem cells, and these effects were observed mostly in CBA/CaJ mice, the strain of mice prone to radiation-induced leukemia (38). Importantly, because hematopoietic stem cells reside at the top of the hematopoietic system hierarchy, epigenetic reprogramming of these cells may lead to epigenetic reprogramming of their differentiated progeny.…”