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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.

SUBMITTER: Dahlet T

PROVIDER: S-EPMC7305168 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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

Dahlet Thomas T Argüeso Lleida Andrea A Al Adhami Hala H Dumas Michael M Bender Ambre A Ngondo Richard P RP Tanguy Manon M Vallet Judith J Auclair Ghislain G Bardet Anaïs F AF Weber Michael M

Nature communications 20200619 1

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 ...[more]

PMID: 32561758

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Project description:Pancreatic cancer (PC) is the fourth leading cause of cancer deaths in the United States with a five-year patient survival rate of only 6%. Early detection and treatment of this disease is hampered due to lack of reliable diagnostic and prognostic markers. Recent studies have shown that dynamic changes in the global DNA methylation and gene expression patterns play key roles in the PC development; hence, provide valuable insights for better understanding the initiation and progression of PC. In the current study, we used DNA methylation, gene expression, copy number, mutational and clinical data from pancreatic patients. We independently investigated the DNA methylation and differential gene expression profiles between normal and tumor samples and correlated methylation levels with gene expression patterns. We observed a total of ~23-thousand differentially methylated CpG sites (Δβ≥0.1) between normal and tumor samples, where majority of the CpG sites are hypermethylated in PC, and this phenomenon is more prominent in the 5'UTRs and promoter regions compared to the gene bodies. Differential methylation is observed in genes associated with the homeobox domain, cell division and differentiation, cytoskeleton, epigenetic regulation and development, pancreatic development and pancreatic signaling and pancreatic cancer core signaling pathways. Correlation analysis suggests that methylation in the promoter region and 5'UTR has mostly negative correlations with gene expression while gene body and 3'UTR associated methylation has positive correlations. Regulatory element analysis suggests that HOX cluster and histone core proteins are upstream regulators of hypomethylation, while SMAD4, STAT4, STAT5B and zinc finger proteins (ZNF) are upstream regulators of hypermethylation. Non-negative matrix factorization (NMF) clustering of differentially methylated sites generated three clusters in PCs suggesting the existence of distinct molecular subtypes. Cluster 1 and cluster 2 showed samples enriched with clinical phenotypes like neoplasm histological grade and pathologic T-stage T3, respectively, while cluster 3 showed the enrichment of samples with neoplasm histological grade G1. To the best of our knowledge, this is the first genome-scale methylome analysis of PC data from TCGA. Our clustering analysis provides a strong basis for future work on the molecular subtyping of epigenetic regulation in pancreatic cancer.

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

Publications

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

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