Regulation of C/EBPdelta-dependent transactivation by histone deacetylases in intestinal epithelial cells.
The C/EBPdelta transcription factor is involved in the positive regulation of the intestinal epithelial cell acute phase response. C/EBPdelta regulation by histone deacetylases (HDACs) during the course of inflammation remains to be determined. Our aim was to examine the effect of HDACs on C/EBPdelta-dependent regulation of haptoglobin, an acute phase protein induced in intestinal epithelial cells in response to pro-inflammatory cytokines. HDAC1, HDAC3, and HDAC4 were expressed in intestinal epithelial cells, as determined by Western blot. GST pull-down assays showed specific HDAC1 interactions with the transcriptional activation and the b-ZIP C/EBPdelta domains, while the co-repressor mSin3A interacts with the C-terminal domain. Immunoprecipitation assays confirmed the interaction between HDAC1 and the N-terminal C/EBPdelta amino acid 36-164 domain. HDAC1 overexpression decreased C/EBPdelta transcriptional activity of the haptoglobin promoter, as assessed by transient transfection and luciferase assays. Chromatin immunoprecipitation analysis showed a displacement of HDAC1 from the haptoglobin promoter in response to inflammatory stimuli and an increased acetylation of histone H3 and H4. HDAC1 silencing by shRNA expression increased both basal and IL-1beta-induced haptoglobin mRNA levels in epithelial intestinal cells. Our results suggest that interactions between C/EBPs and HDAC1 negatively regulate C/EBPdelta-dependent haptoglobin expression in intestinal epithelial cells.
Turgeon
Naomie
N
Département d'anatomie et biologie cellulaire, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, Canada J1H 5N4.
Valiquette
Caroline
C
Blais
Mylène
M
Routhier
Sophie
S
Seidman
Ernest G
EG
Asselin
Claude
C
D000107:Acetylation / Q000187:drug effects; D000210:Acute-Phase Reaction / Q000378:metabolism*; D000818:Animals; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018938:Caco-2 Cells; D006242:Haptoglobins / Q000096:biosynthesis*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects
D006242:Haptoglobins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D053583:Interleukin-1beta; D034741:RNA, Small Interfering; D051743:CCAAT-Enhancer-Binding Protein-delta; D006655:Histone Deacetylases