Cell stem cell, 2016-10, Vol.19 (4), p.491-501
2016
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- Autor(en) / Beteiligte
- Titel
- Dnmt3a and Dnmt3b Associate with Enhancers to Regulate Human Epidermal Stem Cell Homeostasis
- Ist Teil von
- Cell stem cell, 2016-10, Vol.19 (4), p.491-501
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2016
- Quelle
- ScienceDirect
- Beschreibungen/Notizen
- 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. [Display omitted] •Dnmt3a and Dnmt3b associate with the most active enhancers in human epidermal SCs•Their localization is dependent on histone H3K36me3•Dnmt3a and Tet2 promote enhancer DNA hydroxymethylation•Dnmt3a and Dnmt3b are required for enhancer activity and enhancer RNA production Rinaldi et al. show that Dnmt3a and Dnmt3b associate to and activate enhancers. Whereas Dnmt3a induces enhancer DNA hydroxymethylation, Dnmt3b promotes enhancer DNA methylation. Both proteins regulate epidermal SC homeostasis.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1934-5909eISSN: 1875-9777DOI: 10.1016/j.stem.2016.06.020Titel-ID: cdi_csuc_recercat_oai_recercat_cat_2072_314896
- Format
- –
- Schlagworte
- 5-Methylcytosine - analogs & derivatives, 5-Methylcytosine - metabolism, ADN, Base Sequence, Cell Differentiation, Citologia, Cèl·lules mare, Dioxygenases, DNA (Cytosine-5-)-Methyltransferases - metabolism, DNA Methylation - genetics, DNA Methyltransferase 3A, DNA Methyltransferase 3B, DNA-Binding Proteins - metabolism, Enhancer Elements, Genetic - genetics, Epidermal Cells, Epidermis, Histones - metabolism, Homeostasis, Homeòstasi, Humans, Keratinocytes - cytology, Lysine - metabolism, Protein Binding, Proto-Oncogene Proteins - metabolism, Stem Cells - cytology, Stem Cells - metabolism, Transcription Factors - metabolism, Tumor Suppressor Proteins - metabolism