Molecular Determinants of Tbx20 Activity during Cardiac Development
Public Deposited- Last Modified
- March 22, 2019
- Creator
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Kaltenbrun, Erin R.
- Affiliation: College of Arts and Sciences, Department of Biology
- Abstract
- The formation of the heart is a complex process that requires the combinatorial activity of a number of critical cardiogenic transcription factors that function to drive distinct gene subprograms in the developing heart. Tbx20 is a potent activator of cardiac gene expression, and has also been shown to act as a transcriptional repressor in the heart. Precise regulation of Tbx20 expression levels and activity is crucial for normal heart development, as alterations in Tbx20 levels and activity lead to a spectrum of cardiac defects in humans and in animal models. Despite the importance of Tbx20 in heart development, very little is known about how Tbx20 expression is regulated in the heart. Further, the mechanisms by which Tbx20 acts to regulate its target genes are not understood. Here we explore the Tbx20 transcription network, both at the gene and protein level, to identify critical determinants of Tbx20 activity during heart development. We have identified a crucial role for BMP signaling in maintaining Tbx20 cardiac expression during cardiac chamber maturation. This regulation is mediated by a minimal 334 bp regulatory element that is sufficient to drive cardiac expression of Tbx20 in Xenopus, zebrafish, and mouse, indicating that this regulatory pathway is evolutionarily conserved among vertebrates. To begin to decipher how Tbx20 regulates its target genes, we have undertaken a proteomic screen of Tbx20 transcription complexes, both in human cells and mouse embryonic stem cell-derived cardiomyocytes. These studies resulted in the identification of a broad chromatin remodeling network that includes both co-activators and co-repressors. Specifically, Tbx20 directly recruits a Groucho/TLE and histone deacetylase repressor complex through an N-terminal eh1 domain. Additionally, Tbx20 recruits multiple chromatin remodelers including components of the SWI/SNF complex, the NuRD complex, and the INO80 complex. Collectively, these studies suggest that Tbx20 controls gene expression in the developing heart through selective association with distinct chromatin remodeling complexes. This work provides insight into how Tbx20 activity is regulated during cardiac development.
- Date of publication
- August 2013
- DOI
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- Rights statement
- In Copyright
- Advisor
- Conlon, Frank
- Degree
- Doctor of Philosophy
- Graduation year
- 2013
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