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Title: IL-4 orchestrates STAT6-mediated DNA demethylation leading to dendritic cell differentiation
Author: Vento Tormo, Roser
Company, Carlos
Rodríguez-Ubreva, Javier
Rica, Lorenzo de la
Urquiza, José M.
Javierre, Biola M.
Sabarinathan, Radhakrishnan
Luque Gómez, Ana
Esteller, Manel
Aran Perramon, Josep M.
Álvarez-Errico, Damiana
Ballestar Tarín, Esteban
Keywords: ADN
Cèl·lules dendrítiques
Diferenciació cel·lular
Transcripció genètica
Dendritic cells
Cell diferentiation
Genetic transcription
Issue Date: 13-Jan-2016
Publisher: BioMed Central
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 epige- nomes 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.
Note: Reproducció del document publicat a:
It is part of: Genome Biology, 2016, vol. 17, p. 4
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ISSN: 1474-7596
Appears in Collections:Articles publicats en revistes (Ciències Fisiològiques)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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