Coordinated glucocorticoid receptor and MAFB action induces tolerogenesis and epigenome remodeling in dendritic cells
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)
Micheroli, Raphael (University of Zurich)
de la Calle-Fabregat, Carlos (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Li, Tianlu (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Barbisan, Gisela (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Houtman, Miranda (University of Zurich)
Edalat, Sam G. (University of Zurich)
Frank-Bertoncelj, Mojca (University of Zurich)
Ospelt, Caroline (University of Zurich)
Ballestar, Esteban (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)

Fecha:	2022
Resumen:	Glucocorticoids (GCs) exert potent anti-inflammatory effects in immune cells through the glucocorticoid receptor (GR). Dendritic cells (DCs), central actors for coordinating immune responses, acquire tolerogenic properties in response to GCs. Tolerogenic DCs (tolDCs) have emerged as a potential treatment for various inflammatory diseases. To date, the underlying cell type-specific regulatory mechanisms orchestrating GC-mediated acquisition of immunosuppressive properties remain poorly understood. In this study, we investigated the transcriptomic and epigenomic remodeling associated with differentiation to DCs in the presence of GCs. Our analysis demonstrates a major role of MAFB in this process, in synergy with GR. GR and MAFB both interact with methylcytosine dioxygenase TET2 and bind to genomic loci that undergo specific demethylation in tolDCs. We also show that the role of MAFB is more extensive, binding to thousands of genomic loci in tolDCs. Finally, MAFB knockdown erases the tolerogenic properties of tolDCs and reverts the specific DNA demethylation and gene upregulation. The preeminent role of MAFB is also demonstrated in vivo for myeloid cells from synovium in rheumatoid arthritis following GC treatment. Our results imply that, once directly activated by GR, MAFB plays a critical role in orchestrating the epigenomic and transcriptomic remodeling that define the tolerogenic phenotype.
Ayudas:	Agencia Estatal de Investigación SAF2017-88086-R Agencia Estatal de Investigación PID2020- 117212RB-I00 Agencia Estatal de Investigación IFI17/00034 Agencia Estatal de Investigación PID2020-117212RB-I00
Nota:	Altres ajuts: Swiss National Science Foundation (320030 176061)
Derechos:	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, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Adult ; Cells, Cultured ; Dendritic Cells ; Dioxygenases ; DNA Methylation ; DNA-Binding Proteins ; Epigenesis, Genetic ; Female ; Humans ; Immune Tolerance ; MafB Transcription Factor ; Male ; Middle Aged ; Receptors, Glucocorticoid
Publicado en:	Nucleic acids research, Vol. 50 Núm. 1 (january 2022) , p. 108-126, ISSN 1362-4962

DOI: 10.1093/nar/gkab1182
PMID: 34893889

19 p, 5.0 MB

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Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Instituto de Investigación contra la Leucemia Josep Carreras
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