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

Lauren Waldron; Jeffrey D. Steimle; Todd M. Greco; Nicholas C. Gomez; Kerry M. Dorr; Junghun Kweon; Brenda Temple; Xinan Holly Yang; Caralynn M. Wilczewski; Ian J. Davis; Ileana M. Cristea; Ivan P. Moskowitz; Frank L. Conlon

doi:10.1016/j.devcel.2016.01.009

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

Lauren Waldron, Jeffrey D. Steimle, Todd M. Greco, Nicholas C. Gomez, Kerry M. Dorr, Junghun Kweon, Brenda Temple, Xinan Holly Yang, Caralynn M. Wilczewski, Ian J. Davis, Ileana M. Cristea, Ivan P. Moskowitz, Frank L. Conlon

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72 Scopus citations

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.

Original language	English (US)
Pages (from-to)	262-275
Number of pages	14
Journal	Developmental cell
Volume	36
Issue number	3
DOIs	https://doi.org/10.1016/j.devcel.2016.01.009
State	Published - Feb 8 2016

All Science Journal Classification (ASJC) codes

Molecular Biology
General Biochemistry, Genetics and Molecular Biology
Developmental Biology
Cell Biology

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Waldron, L., Steimle, J. D., Greco, T. M., Gomez, N. C., Dorr, K. M., Kweon, J., Temple, B., Yang, X. H., Wilczewski, C. M., Davis, I. J., Cristea, I. M., Moskowitz, I. P., & Conlon, F. L. (2016). The Cardiac TBX5 Interactome Reveals a Chromatin Remodeling Network Essential for Cardiac Septation. Developmental cell, 36(3), 262-275. https://doi.org/10.1016/j.devcel.2016.01.009

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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.",

author = "Lauren Waldron and Steimle, {Jeffrey D.} and Greco, {Todd M.} and Gomez, {Nicholas C.} and Dorr, {Kerry M.} and Junghun Kweon and Brenda Temple and Yang, {Xinan Holly} and Wilczewski, {Caralynn M.} and Davis, {Ian J.} and Cristea, {Ileana M.} and Moskowitz, {Ivan P.} and Conlon, {Frank L.}",

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AU - Dorr, Kerry M.

AU - Kweon, Junghun

AU - Temple, Brenda

AU - Yang, Xinan Holly

AU - Wilczewski, Caralynn M.

AU - Davis, Ian J.

AU - Cristea, Ileana M.

AU - Moskowitz, Ivan P.

AU - Conlon, Frank L.

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N2 - 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.

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

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