title: Tet1 and Tet2 Protect DNA Methylation Canyons against Hypermethylation.
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.
authors.affiliation: Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Wiehle
authors.affiliation: Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Raddatz
authors.affiliation: Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Musch
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Meelad M
authors.initials: MM
authors.lastname: Dawlaty
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Jaenisch
authors.affiliation: Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Lyko
authors.affiliation: Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany a.breiling@dkfz.de.
authors.forename: Achim
authors.identifier: http://orcid.org/0000-0002-7928-299X
authors.initials: A
authors.lastname: Breiling
mesh_terms: D050156:Adipogenesis; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D049308:Dioxygenases; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C540839:TET1 protein, mouse; D049308:Dioxygenases; C551914:Tet2 protein, mouse