Disruption of folate metabolism causes germline epigenetic instability and distinguishes HIRA as a biomarker of maternal transgenerational epigenetic inheritance

Georgina E.T. Blake, Xiaohui Zhao, Hong wa Yung, Graham J Burton, Anne C Ferguson-Smith, Russell S Hamilton, Erica D Watson

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Received Date: 12th May 20

The mechanism behind transgenerational epigenetic inheritance (TEI) is unclear, particularly through the maternal 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. Using genome-wide approaches, we 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 memory of germline methylation defects. One such region is associated with misexpression of the Hira gene at least until the F3 generation in a manner that distinguishes the HIRA histone chaperone as a biomarker of maternal epigenetic inheritance.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

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