Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 4, Pages 1361-1366Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1322921111
Keywords
DNA methylation; DNA hydroxymethylation; epigenetics; DNA demethylation
Categories
Funding
- Leukemia and Lymphoma Society
- Alexander von Humboldt Foundation
- Jane Coffin Childs Memorial Fund for Medical Research
- National Institutes of Health [R01 HL114093, U19 AI100275, R01 GM60398, R01 AI44432, HD065812, CA151535]
- California Institute of Regenerative Medicine [RM1-01729]
- Leukemia and Lymphoma Society Translational Research Program [6187-12]
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Dioxygenases of the Ten-Eleven Translocation (TET) family are 5-methylcytosine oxidases that convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidation products in DNA. We show that Tet1 and Tet2 have distinct roles in regulating 5hmC in mouse embryonic stem cells (mESC). Tet1 depletion diminishes 5hmC levels at transcription start sites (TSS), whereas Tet2 depletion is predominantly associated with decreased 5hmC in gene bodies. Enrichment of 5hmC is observed at the boundaries of exons that are highly expressed, and Tet2 depletion results in substantial loss of 5hmC at these boundaries. In contrast, at promoter/TSS regions, Tet2 depletion results in increased 5hmC, potentially because of the redundant activity of Tet1. Together, the data point to a complex interplay between Tet1 and Tet2 in mESC, and to distinct roles for these two proteins in regulating promoter, exon, and polyadenylation site usage in cells.
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