Dnmt3a and dnmt3b associate with enhancers to regulate human epidermal stem cell homeostasis

Rinaldi, Lorenzo, 1986-; Datta, Debayan; Serrat, Judit; Morey Ramonell, Lluís; Solanas, Guiomar; Avgustinova, Alexandra; Blanco, Enrique; Pons, José Ignacio; Matallanas, David; Kriegsheim, Alex von; Di Croce, Luciano; Aznar Benitah, Salvador

Dnmt3a and dnmt3b associate with enhancers to regulate human epidermal stem cell homeostasis

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dc.contributor.author Rinaldi, Lorenzo, 1986-ca
dc.contributor.author Datta, Debayanca
dc.contributor.author Serrat, Juditca
dc.contributor.author Morey Ramonell, Lluísca
dc.contributor.author Solanas, Guiomarca
dc.contributor.author Avgustinova, Alexandraca
dc.contributor.author Blanco, Enriqueca
dc.contributor.author Pons, José Ignacioca
dc.contributor.author Matallanas, Davidca
dc.contributor.author Kriegsheim, Alex vonca
dc.contributor.author Di Croce, Lucianoca
dc.contributor.author Aznar Benitah, Salvadorca
dc.date.accessioned 2017-11-28T08:19:26Z
dc.date.available 2017-11-28T08:19:26Z
dc.date.issued 2016
dc.description.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.
dc.description.sponsorship The S.A.B. laboratory research is supported by the European Research Council (ERC), the Worldwide Cancer Research Foundation, the Foundation La Marató de TV3, the Spanish Ministry of Economy and Development, the Foundation Vencer el Cancer (‘‘Beat Cancer’’), the Government of Cataluña (SGR and Mario Salvia’ grants), the Foundation Fundación Botín, and the Institute for Research in Biomedicine (IRB-Barcelona). L.R. is a La Caixa Foundation Ph.D. fellow. G.S. was supported by an AXA postdoctoral fellowship. IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain). L.D.C. was supported by grants from the Spanish Ministerio de Educación y Ciencia (SAF2013-48926-P) and the European Commission’s 7th Framework Program 4DCellFate grant number 277899. We are grateful to the Common Fund’s Epigenomic Program from the NIH (USA) for providing the bisulphite whole genome sequencing data of human EpSCs
dc.format.mimetype application/pdfca
dc.identifier.citation Rinaldi L, Datta D, Serrat J, Morey L, Solanas G, Avgustinova A et al. Dnmt3a and dnmt3b associate with enhancers to regulate human epidermal stem cell homeostasis. Cell Stem Cell. 2016 Oct 6;19(4):491-501. DOI: 10.1016/j.stem.2016.06.020
dc.identifier.doi http://dx.doi.org/10.1016/j.stem.2016.06.020
dc.identifier.issn 1934-5909
dc.identifier.uri http://hdl.handle.net/10230/33362
dc.language.iso eng
dc.publisher Elsevierca
dc.relation.ispartof Cell Stem Cell. 2016 Oct 6;19(4):491-501
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2013-48926-P
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/277899
dc.rights © Elsevier This is the published version of an article http://dx.doi.org/10.1016/j.stem.2016.06.020 that appeared in the journal Cell Stem Cell. It is published in an Open Archive under an Elsevier user license. Details of this licence are available here: http://www.elsevier.com/about/open-access/open-access-policies/oa-license-policy/elsevier-user-license
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.subject.other ADN
dc.subject.other Epidermis -- Citologia
dc.subject.other Homeòstasi
dc.subject.other Cèl·lules mare
dc.title Dnmt3a and dnmt3b associate with enhancers to regulate human epidermal stem cell homeostasisca
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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