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

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dc.contributor.author Vento-Tormo, Roser
dc.contributor.author Company Nevado, Juan
dc.contributor.author Rodríguez Ubreva, Javier
dc.contributor.author de la Rica, Lorenzo
dc.contributor.author Urquiza, José M.
dc.contributor.author Javierre, Biola M.
dc.contributor.author Sabarinathan, Radhakrishnan
dc.contributor.author Luque, Ana
dc.contributor.author Esteller, Manel
dc.contributor.author Aran, Josep M.
dc.contributor.author Álvarez Errico, Damiana
dc.contributor.author Ballestar, Esteban
dc.date.accessioned 2016-11-29T12:29:41Z
dc.date.available 2016-11-29T12:29:41Z
dc.date.issued 2016
dc.identifier.citation Vento-Tormo R, Company Nevado J, Rodríguez Ubreva J, de la Rica L, Urquiza JM, Javierre BM, Sabarinathan R, Luque A, Esteller M, Aran JM, Álvarez Errico D, Ballestar E. IL-4 orchestrates STAT6-mediated DNA demethylation leading to dendritic cell differentiation. Genome Biology. 2016; 17:4. DOI: 10.1186/s13059-015-0863-2
dc.identifier.issn 1474-760X
dc.identifier.uri http://hdl.handle.net/10230/27628
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/pdf
dc.language.iso eng
dc.publisher BioMed Central
dc.relation.ispartof Genome Biology. 2016; 17:4
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.
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.title IL-4 orchestrates STAT6-mediated DNA demethylation leading to dendritic cell differentiation
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1186/s13059-015-0863-2
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.relation.projectID info:eu-repo/grantAgreement/EC/FP7/306000
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2014-55942-R
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion


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