LTR retrotransposons transcribed in oocytes drive species-specific and heritable changes in DNA methylation

Julie Brind’Amour,Julien Richard Albert,Hisato Kobayashi,Mohammad M Karimi,Louis Lefebvre,Kenjiro Shirane,Aaron Bogutz,Tomohiro Kono,Tasuku Koike,Matthew C Lorincz,Akihiko Sakashita,Asuka Kamio

doi:10.1038/s41467-018-05841-x

Abstract

De novo DNA methylation (DNAme) during mouse oogenesis occurs within transcribed regions enriched for H3K36me3. As many oocyte transcripts originate in long terminal repeats (LTRs), which are heterogeneous even between closely related mammals, we examined whether species-specific LTR-initiated transcription units (LITs) shape the oocyte methylome. Here we identify thousands of syntenic regions in mouse, rat, and human that show divergent DNAme associated with private LITs, many of which initiate in lineage-specific LTR retrotransposons. Furthermore, CpG island (CGI) promoters methylated in mouse and/or rat, but not human oocytes, are embedded within rodent-specific LITs and vice versa. Notably, at a subset of such CGI promoters, DNAme persists on the maternal genome in fertilized and parthenogenetic mouse blastocysts or in human placenta, indicative of species-specific epigenetic inheritance. Polymorphic LITs are also responsible for disparate DNAme at promoter CGIs in distantly related mouse strains, revealing that LITs also promote intra-species divergence in CGI DNAme.

Highlights

De novo DNA methylation (DNAme) during mouse oogenesis occurs within transcribed regions enriched for H3K36me[3]
To determine the extent to which such CpG island (CGI) methylation might be explained by long terminal repeats (LTRs)-initiated transcription in oocytes, we identified all methylated CGIs (meCGIs) that are embedded within an LTR-initiated transcription units (LITs) in each species
The highest contribution of LITs to de novo DNAme occurs in mouse oocytes, where 40% of all LITs initiate in MTA elements, which are restricted to the mouse genome and active exclusively in the female germline

Summary

Introduction

De novo DNA methylation (DNAme) during mouse oogenesis occurs within transcribed regions enriched for H3K36me[3]. CpG island (CGI) promoters methylated in mouse and/or rat, but not human oocytes, are embedded within rodent-specific LITs and vice versa. Long terminal repeat (LTR) retrotransposons, known as endogenous retroviruses (ERVs), constitute ~10 and ~8% of the mouse and human genome, respectively[1] While their expression is generally suppressed by DNAme and/or repressive histone modifications[2], a subset of ERV subfamilies retain transcriptional activity in specific cell/tissue types[3]. Rat, and human, we identify hundreds of speciesspecific genic and intergenic transcripts, many initiating in solo LTRs private to a single species These LTR-initiated transcription units (LITs) are associated with domains of species-specific DNAme, which in mouse oocytes coincide with transcriptioncoupled H3K36me[3] deposition. We show that LTRs polymorphic between two distantly related mouse strains likely promote strain-specific DNAme states in oocytes, including at CGI promoters

Methods

Results

Conclusion