Reproduction Abstracts

Epimutations are heritable defects in epigenetic programming that do not involve changes in the underlying DNA sequence and may or may not impact gene expression. Epimutations can occur naturally, but are more likely to be induced by environmental factors that disrupt the normal epigenome. Previous studies have shown that the use of assisted reproductive technologies (ART) can induce epimutations in the offspring produced. We chronicled the occurrence of epimtuations in mice produced by natural reproduction, intracytoplasmic sperm injection (ICSI) or somatic cell nuclear transfer (SCNT) by analyzing allele-specific DNA methylation and expression at three imprinted genes, H19, Snrpn and Peg3, in somatic cells from juvenile and adult mice generated by each method. No epimutations were detected in naturally conceived mice, but epimutations were detected in ~50% of ICSI mice and in ~40% of SCNT mice. We allowed the ICSI mice carrying epimutations to reproduce naturally and found no epimutations in the offspring. We then examined germ cells from the ICSI mice and found that the epimutations present in the somatic cells had been corrected by germline-specific epigenetic reprogramming. These are therefore examples of environmentally-induced epimutations that are not transgenerational. Potential differences in these and other environmentally-induced epimutations that do show transgenerational transmission will be discussed. Key differences between transgenerational and non-transgenerational epimutations may include – i) the developmental window during which, or ii) the sequence context in the region of the genome in which the epimutations are induced. Thus, epimutations induced during the period of the ‘epigenetic ground state’ unique to fetal germ cells, and/or those induced in particularly CpG-poor regions of the genome appear to have a higher likelihood of manifesting as transgenerational than those induced at other developmental windows or in other regions of the genome.