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Search Results to Chinmay M Trivedi MD, PhD

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The research goal of the Trivedi lab is to identify cellular processes and regulatory mechanisms involved in cardiac and vascular diseases. 

Although transcription factors involved in cardiovascular development have been described, the closely associated chromatin modifiers of this process remain largely unknown. Histone deacetylases (Hdacs) modify chromatin structure to regulate gene expression in the heart and vasculature. Using knockout and transgenic murine models, we have characterized chromatin modifying enzymes, transcription factors, co-factors, and signaling pathways critical for lymphatic vascular disease (The Journal of Clinical Investigation), mitochondrial and metabolic disease (Science Advances), hepatic vascular hemangiomas (Journal of Experimental Medicine), vascular tumor - Epithelioid Hemangioendothelioma (ATVB), congenital heart disease (JBC), cardiac progenitor cell differentiation (Human Molecular Genetics), cardiomyocyte proliferation (Developmental Cell, JBC), craniofacial defects (Developmental Dynamics), and hypertrophic cardiomyopathy (Nature Medicine).

Recently, the Trivedi lab has established a critical interplay between chromatin modifying enzymes and transcription factors during pathogenesis of congenital heart defects (Human Molecular Genetics). We described a specific and novel function of Hdac3 in cardiac progenitor cells during early murine heart development. TBX5, the causative gene in the Holt-Oram Syndrome, was the first identified single-gene mutation giving rise to congenital heart defects. Our studies reveal a critical mechanistic relationship between TBX5G125R, a gain-of-function mutation identified in patients with Holt-Oram Syndrome, and Hdac3. We uncover a mechanism whereby Hdac3 physically interacts with Tbx5 and modulates its acetylation to repress Tbx5-dependent activation of cardiomyocyte lineage-specific genes.

Interestingly, the human TBX5G125R gain-of- function mutation coincides with the T-box domain required for interaction with Hdac3. TBX5G125R mutation strikingly diminishes its interaction with Hdac3. Further, we demonstrate that HDAC3 deacetylates TBX5 but not TBX5G125R. We identified conserved acetylation sites of TBX5, Lys157 and Lys159, which are important for EP300-mediated acetylation and transcriptional activation. Thus, Hdac3 is required to maintain the pluripotent state of cardiac progenitor cells. These discoveries have opened new areas of investigation and contributed to growing appreciation that HDACs are master regulators of cardiomyocyte homeostasis and function.


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