title: Histone Deacetylase 3 and 4 Complex Stimulates the Transcriptional Activity of the Mineralocorticoid Receptor.
abstract: Histone deacetylases (HDACs) act as corepressors in gene transcription by altering the acetylation of histones, resulting in epigenetic gene silencing. We previously reported that HDAC3 acts as a coactivator of the mineralocorticoid receptor (MR). Although HDAC3 forms complexes with class II HDACs, their potential role in the transcriptional activity of MR is unclear. We hypothesized that HDAC4 of the class II family stimulates the transcriptional activity of MR. The expression of MR target genes was measured by quantitative real-time PCR. MR and RNA polymerase II recruitment to promoters of MR target genes was analyzed by chromatin immunoprecipitation. The association of MR with HDACs was investigated by co-immunoprecipitation. MR acetylation was determined with an anti-acetyl-lysine antibody after immunoprecipitation with an anti-MR antibody. Among the class II HDACs, HDAC4 interacted with both MR and HDAC3 after aldosterone stimulation. The nuclear translocation of HDAC4 was mediated by protein kinase A (PKA) and protein phosphatases (PP). The transcriptional activity of MR was significantly decreased by inhibitors of PKA (H89), PP1/2 (calyculin A), class I HDACs (MS-275), but not class II HDACs (MC1568). MR acetylation was increased by H89, calyculin A, and MS-275, but not by MC1568. Interaction between MR and HDAC3 was significantly decreased by H89, calyculin A, and HDAC4 siRNA. A non-genomic effect of MR via PKA and PP1/2 induced nuclear translocation of HDAC4 to facilitate the interaction between MR and HDAC3. Thus, we have uncovered a crucial role for a class II HDAC in the activation of MR-dependent transcription.
authors: Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea; Cardiovascular Research Institute, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea; Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea.
authors: Hae-Ahm
authors: HA
authors: Lee
authors: Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea.
authors: Min-Ji
authors: MJ
authors: Song
authors: Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea; Cardiovascular Research Institute, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea; Korea Promotion Institute for Traditional Medicine Industry, Gyeongsan, Gyeongbuk 712-260, Republic of Korea.
authors: Young-Mi
authors: YM
authors: Seok
authors: Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea.
authors: Seol-Hee
authors: SH
authors: Kang
authors: Asan Institute for Life Sciences, Asan Medical Center, Seoul 138-736, Republic of Korea; Department of Medicine, University of Ulsan, College of Medicine, Seoul 138-736, Republic of Korea.
authors: Sang-Yeob
authors: SY
authors: Kim
authors: Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea; Cardiovascular Research Institute, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea; Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea.
authors: Inkyeom
authors: I
authors: Kim
mesh_terms: D000107:Acetylation; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008387:Marine Toxins; D010080:Oxazoles / Q000008:administration & dosage; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D000099186:Histone Deacetylase 3
chemical_list: D017868:Cyclic AMP-Dependent Protein Kinases; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D008387:Marine Toxins; D010080:Oxazoles; D010749:Phosphoprotein Phosphatases; D034741:RNA, Small Interfering; D018161:Receptors, Mineralocorticoid; D012097:Repressor Proteins; D000099186:Histone Deacetylase 3; C059041:calyculin A; C400300:HDAC4 protein, human