Dnmt3a and Dnmt3b Associate with Enhancers to Regulate Human Epidermal Stem Cell Homeostasis

Lorenzo Rinaldi, Debayan Datta, Judit Serrat, Lluis Morey, Guiomar Solanas, Alexandra Avgustinova, Enrique Blanco, José Ignacio Pons, David Matallanas, Alex Von Kriegsheim, Luciano Di Croce, Salvador Aznar Benitah

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)491-501
Number of pages11
JournalCell Stem Cell
Volume19
Issue number4
DOIs
StatePublished - Oct 6 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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