Epigenetics in radiation biology: a new research frontier

Abstract

The number of people that receive exposure to ionizing radiation (IR) via occupational, diagnostic, or treatment-related modalities is progressively rising. It is now accepted that the negative consequences of radiation exposure are not isolated to exposed cells or individuals. Exposure to IR can induce genome instability in the germline, and is further associated with transgenerational genomic instability in the offspring of exposed males. The exact molecular mechanisms of transgenerational genome instability have yet to be elucidated, although there is support for it being an epigenetically induced phenomenon. This review is centered on the long-term biological effects associated with IR exposure, mainly focusing on the epigenetic mechanisms (DNA methylation and small RNAs) involved in the molecular etiology of IR-induced genome instability, bystander and transgenerational effects. Here, we present evidence that IR-mediated effects are maintained by epigenetic mechanisms, and demonstrate how a novel, male germline-specific, small RNA pathway is posited to play a major role in the epigenetic inheritance of genome instability.

Low-Dose Gamma Irradiation Enhances Superoxide Anion Production by Nonirradiated Cells Through TGF-β1-Dependent Bystander Signaling

“…This brings vast complexity to the control of gene expression, since each modification exerts its effect differently, and this is further complicated since the effect is determined on the extent of methylation, whether it is mono-, di-or tri-methylation. Histone modification and DNA methylation act together to control the structure of the chromatin and ultimately, gene expression levels (22). Thus, gene expression is a complex process, which is dependent on the DNA sequence itself, the histone-modifying proteins and the methylation state of the gene.…”

“…Methylation is restricted to cytosine (C) nucleotides in the sequence CG (annotated CpG) (16,26 Regulation of proper DNA methylation is vital for proper cell proliferation, cell differentiation and genomic stability. Pathological conditions, which cause global DNA hypomethylation, activate transposable elements, resulting in elevated chromosome breakage, aneuploidy, increased mutation rates and overall genomic instability (22,(27)(28)(29). Furthermore, altered global DNA methylation is a wellknown characteristic of cancer progression.…”

“…The most widely studied epigenetic DNA modification mechanism is cytosine methylation of DNA at the carbon 5 residue to form 5-methyl-cytosine (5meC) (22). The methyl group protrudes from the cytosine nucleotide into the major grove of the DNA and has two main effects: 1. displacement of transcription factors that normally bind DNA; and 2. attraction of methyl binding proteins, which are in turn associated with gene silencing and chromatin compaction (23)(24)(25).…”

“…RISC binds to 3 0 UTR or target mRNAs and represses target mRNA translation. miRNAs are transcribed independently, in clusters, or as polycistron transcripts (22,48).…”

“…Thus, the majority of transcribed genes act as noncoding RNAs, which perform infrastructural (housekeeping role in translation and splicing including ribosomal, transfer and small nuclear RNAs) and regulatory roles (modification of other RNAs by miRNAs, piRNAs, siRNAs, IncRNAs) (46). miRNAs are small (21-25 nt) single-stranded noncoding RNAs that regulate gene expression at the post-transcriptional level by repressing specific mRNAs targets (22,47,48). miRNAs are derived from distinctive hairpin stem loop structures called pre-miRNA.…”