Hypomethylation and genome instability in the germline of exposed parents and their progeny is associated with altered miRNA expression

Abstract

Recent studies suggest that transgenerational genome instability may be epigenetic in nature and mediated via altered DNA methylation and microRNAome. Here, we investigated the nature and mechanisms underlying the disruption of DNA methylation and microRNA expression status in the germline and progeny of exposed parents. We have found that paternal irradiation leads to upregulation of the miR-29 family in the exposed male germline, which causes decreased expression of de novo methyltransferase, DNA methyltransferase 3a, and profound hypomethylation of long interspersed nuclear elements 1 (LINE1) and short interspersed nuclear elements B2 (SINE B2). Epigenetic changes in the male germline further resulted in deleterious effects in the somatic thymus tissue from the progeny of exposed animals, including hypomethylation of LINE1 and SINE B2. Hypomethylation of LINE1 and SINE B2 in the thymus tissue from the progeny was associated with a significant decrease in the levels of lymphoid-specific helicase (LSH) that is crucial for the maintenance of methylation and silencing of repetitive elements. Furthermore, we noted a significant upregulation of miR-468 that targets LSH and leads to its decreased expression in thymus in the progeny of exposed parents. We suggest that miR-468-mediated suppression of LSH leads to aberrant methylation of LINE1 and SINE B2. In summary, altered microRNAome and hypomethylation of retroelements constitute deleterious effects that may significantly influence genome stability of the parental germline and consequently cause genome instability in the progeny.

Epigenetic programming: From gametes to blastocyst

“…One recent example is the observation that hypomethylation of repeated elements in the male germline after irradiation is associated with an increase in miR-29, which downregulates the expression of DNMT3a, resulting in the hypomethylation of repeated elements in the thymus of the offspring (Filkowski et al, 2010). Paramutation is another example; this phenomenon is widely known in plants, but was observed only recently in mice.…”

Radiation-induced genomic instability in Caenorhabditis elegans

“…Because of the apparent lack of a well-defined target, RIGI and the related radiation-induced bystander effect (induction of effects in cells not directly hit by radiation) are commonly called non-targeted effects [5,7,10,11]. Although observations of RIGI are mainly from in vitro studies, inherited germline genomic instability has also been described in rodents [12][13][14][15][16] and even in humans [17][18][19]. However, there is still limited understanding of the mechanisms and consequences of radiation-induced genomic instability in vivo [5,11,20].…”

Role of microRNAs and DNA Methyltransferases in Transmitting Induced Genomic Instability between Cell Generations

“…The Mir-29 family targets DNMT3a and DNMT3b directly, and DNMT1 indirectly (59, 60). Up-regulation of miR-29b can therefore be associated with hypomethylation globally (59, 61) or at specific regions of the genome (19). In our study, miR-29b was up-regulated at 2 days after exposures to TCDD and ionizing radiation, but down-regulation of DNMTs was not detected at the same time point or at 8 days (but transient down-regulation cannot be excluded because of the limited sampling times).…”