title: The zinc finger and C-terminal domains of MTA proteins are required for FOG-2-mediated transcriptional repression via the NuRD complex.
abstract: FOG-2 is a transcriptional co-regulator that is required for cardiac morphogenesis as mice deficient in this factor die during mid-gestation of cardiac malformations. FOG-2 interacts with GATA4 to attenuate GATA4-dependent gene expression. The first 12 amino acids of FOG-2 (the FOG Repression Motif) are necessary to mediate this repression. To determine the mechanism by which the FOG Repression Motif functions, we identified 7 polypeptides from rat cardiac nuclear extracts that co-purified with a GST-FOG-2 fusion protein. All proteins identified are members of the NuRD nucleosome remodeling complex. Using in vitro binding and co-immunoprecipitation assays, we demonstrate that Metastasis-Associated proteins (MTA)-1, 2 and 3 and Retinoblastoma binding proteins RbAp46 and RbAp48 interact with FOG-2, but not with a mutant form of FOG-2 that is unable to repress transcription. Furthermore, we define a novel domain located in the C-terminal portion of MTA-1 that mediates the FOG-2/MTA-1 interaction. We also demonstrate that knockdown of MTA protein expression dramatically impairs the ability of FOG-2 to repress GATA4 activity. Finally, we show that the zinc finger domain of MTA-1 is required for FOG-2-mediated transcriptional repression and that this domain interacts with RbAp46 and RbAp48 subunits of the NuRD complex. Together, these results demonstrate the importance of FOG-2/MTA/RbAp interactions for FOG-2-mediated transcriptional repression and further define the molecular interactions between the FOG Repression Motif and the NuRD complex.
authors: The Committee on Developmental Biology, University of Chicago, Chicago, IL 60637, USA.
authors: Andrea E
authors: AE
authors: Roche
authors: Brett J
authors: BJ
authors: Bassett
authors: Sadhana A
authors: SA
authors: Samant
authors: Wei
authors: W
authors: Hong
authors: Gerd A
authors: GA
authors: Blobel
authors: Eric C
authors: EC
authors: Svensson
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D002846:Chromatography, Affinity; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism*; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; D051379:Mice; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D012097:Repressor Proteins / Q000737:chemistry* / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D015534:Trans-Activators; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism; D014158:Transcription, Genetic; D016335:Zinc Fingers
chemical_list: D004268:DNA-Binding Proteins; C503336:Mta1 protein, mouse; C435499:Mta3 protein, mouse; D009363:Neoplasm Proteins; D021122:Protein Subunits; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; D015534:Trans-Activators; D014157:Transcription Factors; D006655:Histone Deacetylases; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex