Regulation of relB in dendritic cells by means of modulated association of vitamin D receptor and histone deacetylase 3 with the promoter.
The NF-kappaB component RelB is essential for dendritic cell (DC) differentiation and maturation. The vitamin D receptor (VDR) is a nuclear receptor that mediates inhibition of DC maturation and transcriptional repression of relB after engagement of its ligand, 1alpha,25-dihydroxyvitamin D(3), or related analogs (D(3) analogs). Ligand-dependent relB suppression was abolished by a histone deacetylase (HDAC) inhibitor. Constitutive association of VDR with the relB promoter was demonstrated in DCs by chromatin immunoprecipitation. Promoter binding by VDR was enhanced by ligand and reduced by LPS. Association of HDAC3 and HDAC1 with the relB VDR-binding site was observed, but only HDAC3 was reciprocally modulated by D(3) analog and LPS. Overexpression of HDAC3 caused relB promoter suppression, increased sensitivity to D(3) analog, and resistance to LPS. Depletion of HDAC3 attenuated relB suppression by D(3) analog. In vivo, D(3) analog resulted in reduced RelB in DCs from VDR WT mice but not VDR knockout mice. Other NF-lation of RelB and c-Rel in control animals. We conclude that vitamin D-regulated relB transcription in DCs is controlled by chromatin remodeling by means of recruitment of complexes including HDAC3.
Dong
Xiangyang
X
Department of Medicine, Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Lutz
Ward
W
Schroeder
Tania M
TM
Bachman
Lori A
LA
Westendorf
Jennifer J
JJ
Kumar
Rajiv
R
Griffin
Matthew D
MD
D000818:Animals; D001665:Binding Sites; D002762:Cholecalciferol / Q000031:analogs & derivatives / Q000494:pharmacology; D042002:Chromatin Assembly and Disassembly; D003713:Dendritic Cells / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006655:Histone Deacetylases / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D051841:Transcription Factor RelB / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects; D000099186:Histone Deacetylase 3
D002762:Cholecalciferol; D006655:Histone Deacetylases; D008070:Lipopolysaccharides; D018167:Receptors, Calcitriol; D051841:Transcription Factor RelB; D000099186:Histone Deacetylase 3; C497594:Relb protein, mouse