Identification and Characterization of the TBX5 proteome provides mechanistic insight into Holt-Oram syndrome Public Deposited

Downloadable Content

Download PDF
Last Modified
  • March 19, 2019
Creator
  • Waldron, Lauren
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • Congenital heart disease (CHD) remains the most common congenital malformation, with defects in cardiac chamber septation accounting for almost half of all CHD-related deaths in children. The health problem is compounded by the fact that most children are otherwise asymptomatic. The cardiac transcription factor TBX5 has been shown to be causative in patients with septal defects; however, its mechanism of action in normal development and in CHD has not been determined. To begin to address this question we have developed two different model systems that express an epitope-tagged version of TBX5 for in vivo isolation of endogenous tissue. In the Xenopus model, I have developed lines in two different species with the intent to isolate endogenous TBX5 protein complexes. In the mouse model, we have isolated and characterized the endogenous TBX5 cardiac interactome and report that TBX5, long considered to be a cardiac transcriptional activator, interacts biochemically and genetically with the chromatin remodeling repressor machinery of the Nucleosome Remodeling and Deacetylase (NuRD) complex. We report that the TBX5-NuRD interaction is essential for normal heart development and that patients with atrioventricular septal defects (AVSD) have mutations that disrupt the TBX5- NuRD interaction. We identify the direct transcriptional targets of TBX5 and show TBX5 acts to repress expression of neural and cancer associated gene programs in cardiac tissue and that a subset of these genes are disregulated by CHD patient mutations. We also define a new structural-functional domain of TBX5 that is essential for interaction with the NuRD complex and show through phylogenetic analysis that this domain, and hence the interaction with NuRD, evolved during the early diversification of the vertebrates, simultaneous with the evolution of atrial septation. Thus, we report that the TBX5-NuRD interaction identified here plays a central role in cardiac development and in human CHD, as well as in the evolution of the mammalian heart.
Date of publication
Keyword
DOI
Resource type
Rights statement
  • In Copyright
Advisor
  • Conlon, Frank
  • Wang, Greg
  • Graves, Lee
  • Cristea, Ileana
  • Duronio, Robert
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2016
Language
Parents:

This work has no parents.

Items