IL-4 orchestrates STAT6-mediated DNA demethylation leading to dendritic cell differentiation

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  • dc.contributor.author Vento-Tormo, Roserca
  • dc.contributor.author Company Nevado, Juanca
  • dc.contributor.author Rodríguez Ubreva, Javierca
  • dc.contributor.author de la Rica, Lorenzoca
  • dc.contributor.author Urquiza, José M.ca
  • dc.contributor.author Javierre, Biola M.ca
  • dc.contributor.author Sabarinathan, Radhakrishnanca
  • dc.contributor.author Luque, Anaca
  • dc.contributor.author Esteller, Manelca
  • dc.contributor.author Aran, Josep M.ca
  • dc.contributor.author Álvarez Errico, Damianaca
  • dc.contributor.author Ballestar, Estebanca
  • dc.date.accessioned 2016-11-29T12:29:41Z
  • dc.date.available 2016-11-29T12:29:41Z
  • dc.date.issued 2016ca
  • dc.description.abstract Background: The role of cytokines in establishing specific transcriptional programmes in innate immune cells has long been recognized. However, little is known about how these extracellular factors instruct innate immune cell epigenomes to engage specific differentiation states. Human monocytes differentiate under inflammatory conditions into effector cells with non-redundant functions, such as dendritic cells and macrophages. In this context, interleukin 4 (IL-4) and granulocyte macrophage colony-stimulating factor (GM-CSF) drive dendritic cell differentiation, whereas GM-CSF alone leads to macrophage differentiation. Results: Here, we investigate the role of IL-4 in directing functionally relevant dendritic-cell-specific DNA methylation changes. A comparison of DNA methylome dynamics during differentiation from human monocytes to dendritic cells and macrophages identified gene sets undergoing dendritic-cell-specific or macrophage-specific demethylation. Demethylation is TET2-dependent and is essential for acquiring proper dendritic cell and macrophage identity. Most importantly, activation of the JAK3-STAT6 pathway, downstream of IL-4, is required for the acquisition of the dendritic-cell-specific demethylation and expression signature, following STAT6 binding. A constitutively activated form of STAT6 is able to bypass IL-4 upstream signalling and instruct dendritic-cell-specific functional DNA methylation changes. Conclusions: Our study is the first description of a cytokine-mediated sequence of events leading to direct gene-specific demethylation in innate immune cell differentiation.
  • dc.description.sponsorship This work was supported by grant SAF2014-55942-R from the Instituto de Salud Carlos III, organism adscribed to the Ministerio de Economía y Competitividad and confunded by FEDER funds/ European Regional Development Fund (ERDF)- a way to build Europe and Innovation, and the EU FP7 306000 STATegra project. RVT is supported by a PFIS predoctoral fellowship.
  • dc.format.mimetype application/pdfca
  • dc.identifier.citation Vento-Tormo R, Company Nevado J, Rodríguez Ubreva J, de la Rica L, Urquiza JM, Javierre BM et al. IL-4 orchestrates STAT6-mediated DNA demethylation leading to dendritic cell differentiation. Genome Biology. 2016;17:4. DOI: 10.1186/s13059-015-0863-2ca
  • dc.identifier.doi http://dx.doi.org/10.1186/s13059-015-0863-2
  • dc.identifier.issn 1474-760Xca
  • dc.identifier.uri http://hdl.handle.net/10230/27628
  • dc.language.iso engca
  • dc.publisher BioMed Centralca
  • dc.relation.ispartof Genome Biology. 2016;17:4
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/306000ca
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2014-55942-R
  • dc.rights © 2016 Vento-Tormo et al. Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.ca
  • dc.rights.accessRights info:eu-repo/semantics/openAccessca
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Dendritic cell
  • dc.subject.keyword Differentiation
  • dc.subject.keyword DNA demethylation
  • dc.subject.keyword IL-4
  • dc.subject.keyword STAT6
  • dc.subject.keyword TET2
  • dc.title IL-4 orchestrates STAT6-mediated DNA demethylation leading to dendritic cell differentiationca
  • dc.type info:eu-repo/semantics/articleca
  • dc.type.version info:eu-repo/semantics/publishedVersionca

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Articles (Center for Genomic Regulation (CRG))
Articles (Departament de Medicina i Ciències de la Vida)