title: The Cardiac TBX5 Interactome Reveals a Chromatin Remodeling Network Essential for Cardiac Septation.
abstract: Human mutations in the cardiac transcription factor gene TBX5 cause congenital heart disease (CHD), although the underlying mechanism is unknown. We report characterization of the endogenous TBX5 cardiac interactome and demonstrate that TBX5, long considered a transcriptional activator, interacts biochemically and genetically with the nucleosome remodeling and deacetylase (NuRD) repressor complex. Incompatible gene programs are repressed by TBX5 in the developing heart. CHD mis-sense mutations that disrupt the TBX5-NuRD interaction cause depression of a subset of repressed genes. Furthermore, the TBX5-NuRD interaction is required for heart development. Phylogenetic analysis showed that the TBX5-NuRD interaction domain evolved during early diversification of vertebrates, simultaneous with the evolution of cardiac septation. Collectively, this work defines a TBX5-NuRD interaction essential to cardiac development and the evolution of the mammalian heart, and when altered may contribute to human CHD.
authors: University of North Carolina McAllister Heart Institute, UNC-Chapel Hill, Chapel Hill, NC 27599, USA; Integrative Program for Biological & Genome Sciences, UNC-Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Lauren
authors: L
authors: Waldron
authors: Departments of Pediatrics, Pathology, and Human Genetics, The University of Chicago, Chicago, IL 60637, USA.
authors: Jeffrey D
authors: JD
authors: Steimle
authors: Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
authors: Todd M
authors: TM
authors: Greco
authors: Integrative Program for Biological & Genome Sciences, UNC-Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, UNC-Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Nicholas C
authors: NC
authors: Gomez
authors: University of North Carolina McAllister Heart Institute, UNC-Chapel Hill, Chapel Hill, NC 27599, USA; Integrative Program for Biological & Genome Sciences, UNC-Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Kerry M
authors: KM
authors: Dorr
authors: Departments of Pediatrics, Pathology, and Human Genetics, The University of Chicago, Chicago, IL 60637, USA.
authors: Junghun
authors: J
authors: Kweon
authors: R.L. Juliano Structural Bioinformatics Core, Department of Biochemistry and Biophysics, UNC-Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Brenda
authors: B
authors: Temple
authors: Departments of Pediatrics, Pathology, and Human Genetics, The University of Chicago, Chicago, IL 60637, USA.
authors: Xinan Holly
authors: XH
authors: Yang
authors: University of North Carolina McAllister Heart Institute, UNC-Chapel Hill, Chapel Hill, NC 27599, USA; Integrative Program for Biological & Genome Sciences, UNC-Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Caralynn M
authors: CM
authors: Wilczewski
authors: Department of Genetics, UNC-Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, UNC-Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Ian J
authors: IJ
authors: Davis
authors: Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
authors: Ileana M
authors: IM
authors: Cristea
authors: Departments of Pediatrics, Pathology, and Human Genetics, The University of Chicago, Chicago, IL 60637, USA.
authors: Ivan P
authors: IP
authors: Moskowitz
authors: University of North Carolina McAllister Heart Institute, UNC-Chapel Hill, Chapel Hill, NC 27599, USA; Integrative Program for Biological & Genome Sciences, UNC-Chapel Hill, Chapel Hill, NC 27599, USA; Department of Genetics, UNC-Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, UNC-Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biology, UNC-Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: frank_conlon@med.unc.edu.
authors: Frank L
authors: FL
authors: Conlon
mesh_terms: D000818:Animals; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D006321:Heart / Q000196:embryology*; D006801:Humans; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D038081:Organogenesis / Q000235:genetics / Q000502:physiology; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5