Mutation in Folate Metabolism Causes Epigenetic Instability and Transgenerational Effects on Development

Abstract

SUMMARY The importance of maternal folate consumption for normal development is well established. Yet, the molecular mechanism linking folate metabolism to development remains poorly understood. The enzyme methionine synthase reductase (MTRR) is necessary for utilization of methyl groups from the folate cycle. We found that a hypomorphic mutation of the mouse Mtrr gene results in intrauterine growth restriction, developmental delay and congenital malformations including neural tube, heart and placental defects. Importantly, these defects were dependent upon the Mtrr genotypes of the maternal grandparents. Furthermore, we observed widespread epigenetic instability associated with altered gene expression in the placentas of wildtype grandprogeny of Mtrr-deficient maternal grandparents. Embryo transfer experiments revealed two epigenetic mechanisms of Mtrr deficiency in mice: adverse effects on their wildtype daughters’ uterine environment leading to growth defects in wildtype grandprogeny, and the appearance of congenital malformations independent of maternal environment that persist for five generations, likely through transgenerational epigenetic inheritance.

Transgenerational effects of childhood conditions on third generation health and education outcomes

“…On the one hand, there exist a large number of papers which find that environmental shocks lead to epigenetically induced phenotypic changes that become less pronounced from one generation to the next (Geoghegan, 2014, Schmitz et al, 2011, Remy, 2010. On the other hand, there exist several studies which suggest that epigenetic changes may skip the child generation or may predominantly manifest among the grandchildren of the affected individuals (Padmanabhan, 2013, Pembrey et al, 2006, Zeybel, 2012. 6 Therefore, epigenetics potentially has important implications for the effects of health interventions and the economic modeling of human capital formation.…”

Transgenerational Effects of Childhood Conditions on Third Generation Health and Education Outcomes

“…On the one hand, there exist a large number of papers which find that environmental shocks lead to epigenetically induced phenotypic changes that become less pronounced from one generation to the next (Geoghegan, 2014, Schmitz et al, 2011, Remy, 2010. On the other hand, there exist several studies which suggest that epigenetic changes may skip the child generation or may predominantly manifest among the grandchildren of the affected individuals (Padmanabhan, 2013, Pembrey et al, 2006, Zeybel, 2012.…”

Epigenetics and developmental programming of welfare and production traits in farm animals

“…It follows that much of our knowledge of transgenerational epigenetic inheritance in mammals pertains largely to inbred mice, where maternally or paternally induced transmission can come in the form of covalent modifications to DNA and histone methylation (e.g. Padmanabhan et al 2013;Wei et al 2014;Siklenka et al 2015) and altered RNA expression (Wagner et al 2008), often in a breeding scheme-dependent manner (Yuan et al 2015). Not surprisingly, evidence for similar effects occurring in long-lived and out-bred farm animals is scarce, leading González-Recio et al (2015) to question its importance in livestock production.…”