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Dev Cell. 2016 Feb 8;36(3):262-75. doi: 10.1016/j.devcel.2016.01.009.

The Cardiac TBX5 Interactome Reveals a Chromatin Remodeling Network Essential for Cardiac Septation.

Author information

1
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.
2
Departments of Pediatrics, Pathology, and Human Genetics, The University of Chicago, Chicago, IL 60637, USA.
3
Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
4
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.
5
R.L. Juliano Structural Bioinformatics Core, Department of Biochemistry and Biophysics, UNC-Chapel Hill, Chapel Hill, NC 27599, USA.
6
Department of Genetics, UNC-Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, UNC-Chapel Hill, Chapel Hill, NC 27599, USA.
7
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.

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.

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PMID:
26859351
PMCID:
PMC4920128
DOI:
10.1016/j.devcel.2016.01.009
[Indexed for MEDLINE]
Free PMC Article

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