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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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

Biochemistry, Genetics and Molecular Biology(all)
Molecular Biology
Cell Biology
Developmental 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.}",

note = "Funding Information: We thank M. Khohka, J. Wallingford, L. Qian, P. Tandon, and C. Slagle for critical discussions and reading of the manuscript and D. Smalley (UNC-Proteomics Core) for technical help with LTQ-Orbitrap Velos sample analysis. L.W. was supported in part by a grant from the National Institute of General Medical Sciences under award 5T32 GM007092 , AHA 11PRE6110002 , and the UNC Dissertation Completion Fellowship . F.L.C is funded by NIH RO1 HL112618 and HL127640 . I.P.M is funded by R01 HL092153 and R01HL124836 . I.M.C is funded by NIH/NIGMS R01 GM114141 and an NJCCR postdoctoral fellowship to T.M.G. J.D.S. was supported by NIH T32 GM007183 and T32 HL007381 . X.H.Y. is partly supported by NIH award R21CA167305 . We acknowledge the assistance of Lorenzo Pesce for use of the Beagle2 supercomputer, partly supported by NIH under grant 1S10OD018495-01 . Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

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doi = "10.1016/j.devcel.2016.01.009",

language = "English (US)",

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T1 - The Cardiac TBX5 Interactome Reveals a Chromatin Remodeling Network Essential for Cardiac Septation

AU - Waldron, Lauren

AU - Steimle, Jeffrey D.

AU - Greco, Todd M.

AU - Gomez, Nicholas C.

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.

N1 - Funding Information: We thank M. Khohka, J. Wallingford, L. Qian, P. Tandon, and C. Slagle for critical discussions and reading of the manuscript and D. Smalley (UNC-Proteomics Core) for technical help with LTQ-Orbitrap Velos sample analysis. L.W. was supported in part by a grant from the National Institute of General Medical Sciences under award 5T32 GM007092 , AHA 11PRE6110002 , and the UNC Dissertation Completion Fellowship . F.L.C is funded by NIH RO1 HL112618 and HL127640 . I.P.M is funded by R01 HL092153 and R01HL124836 . I.M.C is funded by NIH/NIGMS R01 GM114141 and an NJCCR postdoctoral fellowship to T.M.G. J.D.S. was supported by NIH T32 GM007183 and T32 HL007381 . X.H.Y. is partly supported by NIH award R21CA167305 . We acknowledge the assistance of Lorenzo Pesce for use of the Beagle2 supercomputer, partly supported by NIH under grant 1S10OD018495-01 . Publisher Copyright: © 2016 Elsevier Inc.

PY - 2016/2/8

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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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ER -

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

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