THE REGULATION OF GENE EXPRESSION DURING HEART DEVELOPMENT AND DISEASE Public Deposited

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  • March 21, 2019
Creator
  • Callis, Thomas
    • Affiliation: School of Medicine, Department of Cell Biology and Physiology
Abstract
  • Cardiovascular disease remains one of the most common fatal and disabling disorders in the United States. The development of the heart and pathological processes leading to heart disease are intimately linked to the regulation of gene expression. By understanding the complex genetic and molecular pathways controlling cardiac gene expression, new therapies might be developed for the prevention and treatment of heart disease. My research has focused upon the fundamental mechanisms of transcriptional and post-transcriptional regulation of gene expression. In particular, I have investigated how transcription factors and microRNAs (miRNAs) coordinate cardiac gene expression during development and in disease. Myocardin is a cardiac and smooth muscle-specific transcriptional cofactor for serum response factor (SRF). Myocardin potently activates target gene expression by tethering with SRF bound to SRF-responsive elements. However the upstream signaling pathways controlling myocardin activity and specificity were unknown. Bone Morphogenetic Proteins (BMPs) play important roles in cardiovascular development and I find that Smad1, an effector of the BMP signaling pathway, synergistically activates myocardin-dependent cardiac gene expression. This discovery that myocardin participates in a BMP signaling-dependent cardiac gene transcriptional program helps address how myocardin transactivation of cardiac versus smooth muscle genes is controlled. Much of the current understanding of the genetic pathways controlling cardiac gene expression is based upon studies of transcription factors and regulatory enhancer sequences required for cardiac gene transcription. The discovery of miRNAs has further increased this complexity by adding another layer of regulation at the post-transcriptional level. I show that the miR-208 family, miR-208a and miR-208b, are differentially expressed during heart development, paralleling the expression of their respective host genes alpha- and beta-myosin heavy chain (αMHC and βMHC). Using genetically engineered mice that overproduce miR-208a specifically in the heart or lack miR-208a altogether, I show that miR-208a is an important regulator of cardiac hypertrophy and cardiac conduction. Collectively, my studies of the transcription factor myocardin and the miR-208 family extend the current understanding of how cardiac gene expression is regulated during heart development and disease.
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  • In Copyright
Advisor
  • Bankaitis, Vytas A.
  • Beckers, Con
  • Conlon, Frank
  • Wang, Da-Zhi
  • Majesky, Mark W.
  • Hammond, Scott
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2008
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