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

TitleThe Cardiac TBX5 Interactome Reveals a Chromatin Remodeling Network Essential for Cardiac Septation.
Publication TypeJournal Article
Year of Publication2016
AuthorsWaldron, L, Steimle, JD, Greco, TM, Gomez, NC, Dorr, KM, Kweon, J, Temple, B, Yang, XHolly, Wilczewski, CM, Davis, IJ, Cristea, IM, Moskowitz, IP, Conlon, FL
JournalDev Cell
Volume36
Issue3
Pagination262-75
Date Published2016 Feb 8
ISSN1878-1551
KeywordsAnimals, Chromatin Assembly and Disassembly, Gene Expression Regulation, Developmental, Heart, Humans, Mice, Transgenic, Myocardium, Organogenesis, T-Box Domain Proteins, Transcription, Genetic
Abstract

<p>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.</p>

DOI10.1016/j.devcel.2016.01.009
Alternate JournalDev. Cell
PubMed ID26859351
PubMed Central IDPMC4920128
Grant List1S10OD018495-01 / OD / NIH HHS / United States
5T32 GM007092 / GM / NIGMS NIH HHS / United States
HL127640 / HL / NHLBI NIH HHS / United States
NIH RO1HL112618 / HL / NHLBI NIH HHS / United States
NIH T32 GM007183 / GM / NIGMS NIH HHS / United States
NIH/NIGMS R01 GM114141 / / PHS HHS / United States
P40 OD010997 / OD / NIH HHS / United States
R01 HL092153 / HL / NHLBI NIH HHS / United States
R01 HL092153 / HL / NHLBI NIH HHS / United States
R01 HL112618 / HL / NHLBI NIH HHS / United States
R01 HL127640 / HL / NHLBI NIH HHS / United States
R01HL124836 / HL / NHLBI NIH HHS / United States
R21 CA167305 / CA / NCI NIH HHS / United States
R21CA167305 / CA / NCI NIH HHS / United States
T32 HL007381 / HL / NHLBI NIH HHS / United States
T32 HL007381 / HL / NHLBI NIH HHS / United States