Tet1 and Tet2 protect DNA methylation canyons against hypermethylation

Laura Wiehle, Günter Raddatz, Tanja Musch, Meelad M. Dawlaty, Rudolf Jaenisch, Frank Lyko, Achim Breiling

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

DNA methylation is a dynamic epigenetic modification with an important role in cell fate specification and reprogramming. The Ten eleven translocation (Tet) family of enzymes converts 5-methylcytosine to 5-hydroxymethylcytosine, which promotes passive DNA demethylation and functions as an intermediate in an active DNA demethylation process. Tet1/Tet2 double-knockout mice are characterized by developmental defects and epigenetic instability, suggesting a requirement for Tet-mediated DNA demethylation for the proper regulation of gene expression during differentiation. Here, we used whole-genome bisulfite and transcriptome sequencing to characterize the underlying mechanisms. Our results uncover the hypermethylation of DNA methylation canyons as the genomic key feature of Tet1/Tet2 double-knockout mouse embryonic fibroblasts. Canyon hypermethylation coincided with disturbed regulation of associated genes, suggesting a mechanistic explanation for the observed Tet-dependent differentiation defects. Based on these results, we propose an important regulatory role of Tet-dependent DNA demethylation for the maintenance of DNA methylation canyons, which prevents invasive DNA methylation and allows functional regulation of canyon-associated genes.

Original languageEnglish (US)
Pages (from-to)452-461
Number of pages10
JournalMolecular and Cellular Biology
Volume36
Issue number3
DOIs
StatePublished - 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Wiehle, L., Raddatz, G., Musch, T., Dawlaty, M. M., Jaenisch, R., Lyko, F., & Breiling, A. (2016). Tet1 and Tet2 protect DNA methylation canyons against hypermethylation. Molecular and Cellular Biology, 36(3), 452-461. https://doi.org/10.1128/MCB.00587-15