title: Involvement of the histone deacetylase SIRT1 in chicken ovalbumin upstream promoter transcription factor (COUP-TF)-interacting protein 2-mediated transcriptional repression.
abstract: Chicken ovalbumin upstream promoter transcription factor (COUP-TF)-interacting proteins 1 and 2 (CTIP1 and CTIP2) enhance transcriptional repression mediated by COUP-TF II and have been implicated in hematopoietic cell development and malignancies. CTIP1 and CTIP2 are also sequence-specific DNA-binding proteins that repress transcription through direct, COUP-TF-in-dependent binding to a GC-rich response element. CTIP1- and CTIP2-mediated transcriptional repression is insensitive to trichostatin A, an inhibitor of known class I and II histone deacetylases. However, chromatin immunoprecipitation assays revealed that expression of CTIP2 in mammalian cells resulted in deacetylation of histones H3 and/or H4 that were associated with the promoter region of a reporter gene. CTIP2-mediated transcriptional repression, as well as deacetylation of promoter-associated histones H3/H4 in CTIP2-transfected cells, was reversed by nicotinamide, an inhibitor of class III histone deacetylases such as the mammalian homologs of yeast Silent Information Regulator 2 (Sir2). The human homolog of yeast Sir2, SIRT1, was found to interact directly with CTIP2 and was recruited to the promoter template in a CTIP2-dependent manner. Moreover, SIRT1 enhanced the deacetylation of template-associated histones H3/H4 in CTIP2-transfected cells, and stimulated CTIP2-dependent transcriptional repression. Finally, endogenous SIRT1 and CTIP2 co-purified from Jurkat cell nuclear extracts in the context of a large (1-2 mDa) complex. These findings implicate SIRT1 as a histone H3/H4 deacetylase in mammalian cells and in transcriptional repression mediated by CTIP2.
authors.affiliation: Laboratory of Molecular Pharmacology, Department of Pharmaceutical Sciences, College of Pharmacy, Environmental Health Sciences Center, Oregon State University, Corvallis, Oregon 97331, USA.
authors.forename: Thanaset
authors.initials: T
authors.lastname: Senawong
authors.forename: Valerie J
authors.initials: VJ
authors.lastname: Peterson
authors.forename: Dorina
authors.initials: D
authors.lastname: Avram
authors.forename: David M
authors.initials: DM
authors.lastname: Shepherd
authors.forename: Roy A
authors.initials: RA
authors.lastname: Frye
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
authors.forename: Mark
authors.initials: M
authors.lastname: Leid
mesh_terms: D051836:COUP Transcription Factors; D002352:Carrier Proteins; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020868:Gene Silencing; D017930:Genes, Reporter; D005982:Glutathione Transferase / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D015151:Immunoblotting; D019169:Jurkat Cells; D009243:NAD / Q000378:metabolism; D009363:Neoplasm Proteins / Q000737:chemistry / Q000502:physiology; D009536:Niacinamide / Q000494:pharmacology; D009687:Nuclear Proteins; D011233:Precipitin Tests; D011485:Protein Binding; D011987:Receptors, Steroid; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000502:physiology*; D056564:Sirtuin 1; D037761:Sirtuins / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D025521:Tumor Suppressor Proteins
chemical_list: C486563:BCL11A protein, human; C479740:BCL11B protein, human; D051836:COUP Transcription Factors; D002352:Carrier Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011987:Receptors, Steroid; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D009243:NAD; D009536:Niacinamide; C012589:trichostatin A; D004247:DNA; D005982:Glutathione Transferase; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins; D006655:Histone Deacetylases