Defective folate metabolism causes germline epigenetic instability and distinguishes Hira as a phenotype inheritance biomarker

ABSTRACT The mechanism behind transgenerational epigenetic inheritance (TEI) is unclear, particularly through the maternal grandparental line. We previously showed that disruption of folate metabolism in mice by the Mtrrgt hypomorphic mutation results in TEI of congenital malformations. Either maternal grandparent can initiate this phenomenon, which persists for at least four wildtype generations. In this work, we use a genome-wide approach to reveal genetic stability in the Mtrrgt model and epigenome-wide differential DNA methylation in the germline of Mtrr+/gt maternal grandfathers. While epigenetic reprogramming occurs, wildtype grandprogeny and great grandprogeny exhibit transcriptional memory of germline methylation defects. One region encompasses the Hira gene, which is misexpressed in embryos at least until the F3 generation in a manner that distinguishes Hira transcript expression as a biomarker of maternal phenotypic inheritance.