Genome-wide analysis in the mouse embryo reveals the importance of DNA methylation for transcription integrity

Abstract

Mouse embryos acquire global DNA methylation of their genome during implantation. However the exact roles of DNA methyltransferases (DNMTs) in embryos have not been studied comprehensively. Here we systematically analyze the consequences of genetic inactivation of Dnmt1, Dnmt3a and Dnmt3b on the methylome and transcriptome of mouse embryos. We find a strict division of function between DNMT1, responsible for maintenance methylation, and DNMT3A/B, solely responsible for methylation acquisition in development. By analyzing severely hypomethylated embryos, we uncover multiple functions of DNA methylation that is used as a mechanism of repression for a panel of genes including not only imprinted and germline genes, but also lineage-committed genes and 2-cell genes. DNA methylation also suppresses multiple retrotransposons and illegitimate transcripts from cryptic promoters in transposons and gene bodies. Our work provides a thorough analysis of the roles of DNA methyltransferases and the importance of DNA methylation for transcriptome integrity in mammalian embryos.

A DNA methylation state transition model reveals the programmed epigenetic heterogeneity in human pre-implantation embryos

“…To further evaluate the interpretability of parameters, we extended the application of MethylTransition to bulk cell-level BS-seq data with methylation enzymes knockout (see the “ Methods ” section for details). We collected the BS-seq data in wild-type and two types of enzyme-knockout mouse embryos ( Dnmt1 −/− , Dnmt3a/b −/− ) at the E8.5 stage [ 30 ]. The Dnmt1 −/− embryos displayed the smallest p , and the Dnmt3a/b −/− embryos showed the smallest u , which are in agreement with the known function of these DNMTs (Additional file 1 : Fig.…”

“…The public scRNA-seq data of mouse early embryos used in this paper are available at GEO under accession GSE45719 [ 63 ], GSE65160 [ 64 ], and GSE98150 [ 65 ]. The public BS-seq data of mouse embryos with methylation enzyme knockout used in this paper are available at GEO under accession GSE130735 [ 30 ]. The public BS-seq data of zebrafish embryos with methylation enzyme knockout used in this paper are available at GEO under accession GSE68087 [ 66 ].…”

Staying true to yourself: mechanisms of DNA methylation maintenance in mammals

“…Part or all of the methylation machinery has been lost independently in multiple phyla ( 1–4 ), for instance there is no CpG methylation in common model organisms such as Saccharomyces cerevisiae , Caenorhabditis elegans or Drosophila melanogaster , yet among eukaryotes, many species display DNA methylation ( 5–7 ). In mammals, which will be the focus of this review, DNA methylation is essential for embryonic development and cellular function ( 8–10 ).…”

Interplay between Histone and DNA Methylation Seen through Comparative Methylomes in Rare Mendelian Disorders

“…In mammals, the covalent transfer of a methyl group onto DNA occurs mainly in a CpG context. DNA methylation (DNAme) has been assigned major roles in fundamental biological processes that include the regulation of gene expression programs and the silencing of inactive-X chromosome in females, imprinted genes, transposons, and repetitive elements [ 2 , 3 , 4 ]. DNAme is catalyzed by DNA methyltransferases (DNMTs) among which DNMT3A and DNMT3B add methyl groups de novo to unmethylated DNA, whereas DNMT1 maintains DNAme patterns from hemi-methylated DNA after DNA replication has occurred [ 5 , 6 ].…”

“…Not surprisingly, DNAme and its machinery are essential for the healthy development of mammals and, more generally, throughout life. Evidence comes from animal models [ 4 , 5 , 27 ], but also from human diseases where DNAme landscapes or the DNAme machinery itself are often impaired, such as in cancer or other complex multifactorial disease [ 28 , 29 ]. In addition, the expanding class of genetic diseases caused by rare pathogenic variants of the epigenetic machinery has led to a real breakthrough in the field in allowing to infer direct connections between epigenetic actors, multi-loci alterations and the emergence of disease phenotypes [ 30 , 31 , 32 ].…”