There are numerous benefits to elucidating how our environment affects our health: from a greater understanding of adaptation to disease prevention. Evidence shows that stressors we are exposed to during our lifetime might cause disease in our descendants. Transgenerational epigenetic inheritance involves the transmission of 'information' over multiple generations via the gametes independent of the DNA base sequence. Despite extensive research, the epigenetic mechanisms remain unclear. Analysis of model organisms exposed to environmental insults (e.g., diet manipulation, stress, toxin exposure) or carrying mutations in the epigenetic regulatory machinery indicates that inheritance of altered DNA methylation, histone modifications, or non-coding RNAs are key mechanisms. Tracking inherited epigenetic information and its effects for multiple generations is a significant challenge to overcome.

The mechanism behind transgenerational epigenetic inheritance is unclear, particularly through the maternal grandparental line. We previously showed that disruption of folate metabolism in mice by the Mtrr hypomorphic mutation results in transgenerational epigenetic inheritance of congenital malformations. Either maternal grandparent can initiate this phenomenon, which persists for at least four wildtype generations. Here, we use genome-wide approaches to reveal genetic stability in the Mtrr model and genome-wide differential DNA methylation in the germline of Mtrr mutant maternal grandfathers. We observe that, while epigenetic reprogramming occurs, wildtype grandprogeny and great grandprogeny exhibit transcriptional changes that correlate with germline methylation defects. One region encompasses the Hira gene, which is misexpressed in embryos for at least three wildtype generations in a manner that distinguishes Hira transcript expression as a biomarker of maternal phenotypic inheritance.

No abstract

The exposure to adverse environmental conditions (e.g. poor nutrition) may lead to increased disease risk in an individual and their descendants. In some cases, the results may be sexually dimorphic. A range of phenotypes has been associated with deficiency in or defective metabolism of the vitamin folate. However, the molecular mechanism linking folate metabolism to development is still not well defined nor is it clear whether phenotypes are sex-specific. The enzyme methionine synthase reductase (MTRR) is required for the progression of folate metabolism and the utilization of methyl groups from the folate cycle. Previously, we showed that the hypomorphic Mtrrgt mutation in mice results in metabolic disruption, epigenetic instability, and a wide spectrum of developmental phenotypes (e.g. growth defects, congenital malformations) at midgestation that appear in subsequent wild-type generations. This transgenerational effect only occurs through the maternal lineage. Here, we explore whether the phenotypes that result from either intrinsic or ancestral Mtrr deficiency are sexually dimorphic. We found that no sexual dimorphism is apparent in either situation when the phenotypes were broadly or specifically defined. However, when we focused on the group of phenotypically normal conceptuses derived from maternal grandparental Mtrr deficiency, we observed an apparent increase in placental efficiency in each subsequent generation leading to F4 generation female embryos that weigh more than controls. These data suggest that ancestral abnormal folate metabolism may lead to male grandprogeny that are less able to adapt or female grandprogeny that are programmed to become more sensitive to folate availability in subsequent generations.