SIRT1/2 orchestrate acquisition of DNA methylation and loss of histone H3 activating marks to prevent premature activation of inflammatory genes in macrophages
Li, Tianlu (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Garcia-Gomez, Antonio (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Morante-Palacios, Octavio (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Ciudad, Laura (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Özkaramehmet, S. (Institut d'Investigació Biomèdica de Bellvitge)
Van Dijck, E. (Institut d'Investigació Biomèdica de Bellvitge)
Rodríguez-Ubreva, Javier (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Vaquero, Alejandro (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Ballestar, Esteban (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Universitat Autònoma de Barcelona

Date:	2020
Abstract:	Sirtuins 1 and 2 (SIRT1/2) are two NAD-dependent deacetylases with major roles in inflammation. In addition to deacetylating histones and other proteins, SIRT1/2-mediated regulation is coupled with other epigenetic enzymes. Here, we investigate the links between SIRT1/2 activity and DNA methylation in macrophage differentiation due to their relevance in myeloid cells. SIRT1/2 display drastic upregulation during macrophage differentiation and their inhibition impacts the expression of many inflammation-related genes. In this context, SIRT1/2 inhibition abrogates DNA methylation gains, but does not affect demethylation. Inhibition of hypermethylation occurs at many inflammatory loci, which results in more drastic upregulation of their expression upon macrophage polarization following bacterial lipopolysaccharide (LPS) challenge. SIRT1/2-mediated gains of methylation concur with decreases in activating histone marks, and their inhibition revert these histone marks to resemble an open chromatin. Remarkably, specific inhibition of DNA methyltransferases is sufficient to upregulate inflammatory genes that are maintained in a silent state by SIRT1/2. Both SIRT1 and SIRT2 directly interact with DNMT3B, and their binding to proinflammatory genes is lost upon exposure to LPS or through pharmacological inhibition of their activity. In all, we describe a novel role for SIRT1/2 to restrict premature activation of proinflammatory genes.
Grants:	Ministerio de Ciencia e Innovación SAF2014-55942-R Ministerio de Ciencia e Innovación SAF2017-88086-R
Note:	Altres ajuts: CERCA Programme/Generalitat de Catalunya; [...].
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Published in:	Nucleic acids research, Vol. 48 Núm. 2 (24 2020) , p. 665-681, ISSN 1362-4962

DOI: 10.1093/nar/gkz1127
PMID: 31799621

17 p, 3.2 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Josep Carreras Leukaemia Research Institute
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Articles > Published articles