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


Change log
Authors
Blake, Georgina E. T. 
Yung, Hong wa 
Ferguson-Smith, Anne C. 
Abstract

Abstract: 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.

Description

Funder: Center for Trophoblast Research

Keywords
Article, /631/136/2442, /631/208/176, /631/443/319, /45/23, /45/88, /45/90, /38/22, /64/60, /82/80, /82/58, article
Journal Title
Nature Communications
Conference Name
Journal ISSN
2041-1723
Volume Title
12
Publisher
Nature Publishing Group UK
Sponsorship
RCUK | Medical Research Council (MRC) (MR/J001597)