1. Dnmt3a and Dnmt3b Associate with Enhancers to Regulate Human Epidermal Stem Cell Homeostasis.
- Author
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Rinaldi L, Datta D, Serrat J, Morey L, Solanas G, Avgustinova A, Blanco E, Pons JI, Matallanas D, Von Kriegsheim A, Di Croce L, and Benitah SA
- Subjects
- 5-Methylcytosine analogs & derivatives, 5-Methylcytosine metabolism, Base Sequence, Cell Differentiation, DNA Methylation genetics, DNA Methyltransferase 3A, DNA-Binding Proteins metabolism, Dioxygenases, Histones metabolism, Humans, Keratinocytes cytology, Lysine metabolism, Protein Binding, Proto-Oncogene Proteins metabolism, Transcription Factors metabolism, Tumor Suppressor Proteins metabolism, DNA Methyltransferase 3B, DNA (Cytosine-5-)-Methyltransferases metabolism, Enhancer Elements, Genetic genetics, Epidermal Cells, Homeostasis, Stem Cells cytology, Stem Cells metabolism
- 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., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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