PMID- 34893889
OWN - NLM
STAT- MEDLINE
DCOM- 20220217
LR  - 20220217
IS  - 1362-4962 (Electronic)
IS  - 0305-1048 (Print)
IS  - 0305-1048 (Linking)
VI  - 50
IP  - 1
DP  - 2022 Jan 11
TI  - Coordinated glucocorticoid receptor and MAFB action induces tolerogenesis and 
      epigenome remodeling in dendritic cells.
PG  - 108-126
LID - 10.1093/nar/gkab1182 [doi]
AB  - 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.
CI  - (c) The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic 
      Acids Research.
FAU - Morante-Palacios, Octavio
AU  - Morante-Palacios O
AD  - Epigenetics and Immune Disease Group, Josep Carreras Research Institute (IJC), 
      08916 Badalona, Barcelona, Spain.
AD  - Germans Trias i Pujol Research Institute (IGTP), 08916 Badalona, Barcelona, 
      Spain.
FAU - Ciudad, Laura
AU  - Ciudad L
AD  - Epigenetics and Immune Disease Group, Josep Carreras Research Institute (IJC), 
      08916 Badalona, Barcelona, Spain.
FAU - Micheroli, Raphael
AU  - Micheroli R
AD  - Center of Experimental Rheumatology, Department of Rheumatology, University 
      Hospital Zurich, University of Zurich, Zurich, Switzerland.
FAU - de la Calle-Fabregat, Carlos
AU  - de la Calle-Fabregat C
AD  - Epigenetics and Immune Disease Group, Josep Carreras Research Institute (IJC), 
      08916 Badalona, Barcelona, Spain.
FAU - Li, Tianlu
AU  - Li T
AD  - Epigenetics and Immune Disease Group, Josep Carreras Research Institute (IJC), 
      08916 Badalona, Barcelona, Spain.
FAU - Barbisan, Gisela
AU  - Barbisan G
AD  - Epigenetics and Immune Disease Group, Josep Carreras Research Institute (IJC), 
      08916 Badalona, Barcelona, Spain.
FAU - Houtman, Miranda
AU  - Houtman M
AD  - Center of Experimental Rheumatology, Department of Rheumatology, University 
      Hospital Zurich, University of Zurich, Zurich, Switzerland.
FAU - Edalat, Sam G
AU  - Edalat SG
AD  - Center of Experimental Rheumatology, Department of Rheumatology, University 
      Hospital Zurich, University of Zurich, Zurich, Switzerland.
FAU - Frank-Bertoncelj, Mojca
AU  - Frank-Bertoncelj M
AD  - Center of Experimental Rheumatology, Department of Rheumatology, University 
      Hospital Zurich, University of Zurich, Zurich, Switzerland.
FAU - Ospelt, Caroline
AU  - Ospelt C
AD  - Center of Experimental Rheumatology, Department of Rheumatology, University 
      Hospital Zurich, University of Zurich, Zurich, Switzerland.
FAU - Ballestar, Esteban
AU  - Ballestar E
AUID- ORCID: 0000-0002-1400-2440
AD  - Epigenetics and Immune Disease Group, Josep Carreras Research Institute (IJC), 
      08916 Badalona, Barcelona, Spain.
AD  - Germans Trias i Pujol Research Institute (IGTP), 08916 Badalona, Barcelona, 
      Spain.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Nucleic Acids Res
JT  - Nucleic acids research
JID - 0411011
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (MAFB protein, human)
RN  - 0 (MafB Transcription Factor)
RN  - 0 (Receptors, Glucocorticoid)
RN  - EC 1.13.11.- (Dioxygenases)
RN  - EC 1.13.11.- (TET2 protein, human)
SB  - IM
MH  - Adult
MH  - Cells, Cultured
MH  - DNA Methylation
MH  - DNA-Binding Proteins/metabolism
MH  - Dendritic Cells/*immunology
MH  - Dioxygenases/metabolism
MH  - *Epigenesis, Genetic
MH  - Female
MH  - Humans
MH  - *Immune Tolerance
MH  - MafB Transcription Factor/genetics/*metabolism
MH  - Male
MH  - Middle Aged
MH  - Receptors, Glucocorticoid/*metabolism
PMC - PMC8754638
EDAT- 2021/12/12 06:00
MHDA- 2022/02/19 06:00
PMCR- 2021/12/10
CRDT- 2021/12/11 06:14
PHST- 2021/11/16 00:00 [accepted]
PHST- 2021/11/08 00:00 [revised]
PHST- 2021/09/20 00:00 [received]
PHST- 2021/12/12 06:00 [pubmed]
PHST- 2022/02/19 06:00 [medline]
PHST- 2021/12/11 06:14 [entrez]
PHST- 2021/12/10 00:00 [pmc-release]
AID - 6459126 [pii]
AID - gkab1182 [pii]
AID - 10.1093/nar/gkab1182 [doi]
PST - ppublish
SO  - Nucleic Acids Res. 2022 Jan 11;50(1):108-126. doi: 10.1093/nar/gkab1182.