One-carbon metabolism is required for epigenetic stability in the mouse placenta

Claire E Senner; Ziqi Dong; Malwina Prater; Miguel R Branco; Erica D Watson

doi:10.3389/fcell.2023.1209928

One-carbon metabolism is required for epigenetic stability in the mouse placenta

Front Cell Dev Biol. 2023 Jun 27:11:1209928. doi: 10.3389/fcell.2023.1209928. eCollection 2023.

Authors

Claire E Senner^{1

2}, Ziqi Dong², Malwina Prater^{1

3}, Miguel R Branco⁴, Erica D Watson^{1

2}

Affiliations

¹ Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom.
² Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, United Kingdom.
³ Department of Genetics, University of Cambridge, Cambridge, United Kingdom.
⁴ Centre for Genomics and Child Health, Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.

Abstract

One-carbon metabolism, including the folate cycle, has a crucial role in fetal development though its molecular function is complex and unclear. The hypomorphic Mtrr ^gt allele is known to disrupt one-carbon metabolism, and thus methyl group availability, leading to several developmental phenotypes (e.g., neural tube closure defects, fetal growth anomalies). Remarkably, previous studies showed that some of the phenotypes were transgenerationally inherited. Here, we explored the genome-wide epigenetic impact of one-carbon metabolism in placentas associated with fetal growth phenotypes and determined whether specific DNA methylation changes were inherited. Firstly, methylome analysis of Mtrr ^gt/gt homozygous placentas revealed genome-wide epigenetic instability. Several differentially methylated regions (DMRs) were identified including at the Cxcl1 gene promoter and at the En2 gene locus, which may have phenotypic implications. Importantly, we discovered hypomethylation and ectopic expression of a subset of ERV elements throughout the genome of Mtrr ^gt/gt placentas with broad implications for genomic stability. Next, we determined that known spermatozoan DMRs in Mtrr ^gt/gt males were reprogrammed in the placenta with little evidence of direct or transgenerational germline DMR inheritance. However, some spermatozoan DMRs were associated with placental gene misexpression despite normalisation of DNA methylation, suggesting the inheritance of an alternative epigenetic mechanism. Integration of published wildtype histone ChIP-seq datasets with Mtrr ^gt/gt spermatozoan methylome and placental transcriptome datasets point towards H3K4me3 deposition at key loci. These data suggest that histone modifications might play a role in epigenetic inheritance in this context. Overall, this study sheds light on the mechanistic complexities of one-carbon metabolism in development and epigenetic inheritance.

Keywords: DNA methylation; MTRR; epigenetic inheritance; folate; histone methylation; sperm; transposable elements; trophoblast.

Grants and funding

This work was supported by a Next Generation Fellowship from the Centre for Trophoblast Research (to CS) and the Lister Institute for Preventative Medicine (to EW). ZD was funded by a Wellcome Trust DTP studentship in Developmental Mechanisms (222275/Z/20/Z).