Journal
CELL STEM CELL
Volume 19, Issue 4, Pages 491-501Publisher
CELL PRESS
DOI: 10.1016/j.stem.2016.06.020
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Funding
- European Research Council (ERC)
- Worldwide Cancer Research Foundation
- Foundation La Marato de TV3
- Spanish Ministry of Economy and Development
- Foundation Vencer el Cancer (Beat Cancer)
- Government of Cataluna
- Foundation Fundacion Botin
- Institute for Research in Biomedicine (IRB-Barcelona)
- AXA
- MINECO (Government of Spain)
- Spanish Ministerio de Educacion y Ciencia [SAF2013-48926-P]
- European Commission [277899]
- Worldwide Cancer Research [10-0050] Funding Source: researchfish
- ICREA Funding Source: Custom
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The genome-wide localization and function of endogenous Dnmt3a and Dnmt3b in adult stem cells are unknown. Here, we show that in human epidermal stem cells, the two proteins bind in a histone H3K36me3-dependent manner to the most active enhancers and are required to produce their associated enhancer RNAs. Both proteins prefer super-enhancers associated to genes that either define the ectodermal lineage or establish the stem cell and differentiated states. However, Dnmt3a and Dnmt3b differ in their mechanisms of enhancer regulation: Dnmt3a associates with p63 to maintain high levels of DNA hydroxymethylation at the center of enhancers in a Tet2-dependent manner, whereas Dnmt3b promotes DNA methylation along the body of the enhancer. Depletion of either protein inactivates their target enhancers and profoundly affects epidermal stem cell function. Altogether, we reveal novel functions for Dnmt3a and Dnmt3b at enhancers that could contribute to their roles in disease and tumorigenesis.
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