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Enigma – Histone Deacetylase protein complex controls cardiac hypertrophy (ENIGMA)
Start date: Jul 1, 2012, End date: Jun 30, 2016 PROJECT  FINISHED 

"A variety of cardiovascular disorders provoke the heart to enlarge through hypertrophic growth of cardiomyocytes, resulting in heart failure and sudden death. Based on in vivo and in vitro models of cardiac hypertrophy, it is apparent that histone-modifying enzymes act as key regulators of cardiac growth. Although their upstream regulation has been studied, the mechanism whereby class IIa Histone deacetylases (HDACs) repress transcription has not been elucidated.In preliminary studies, we performed an association screen with the Class IIa HDAC4 and a heart cDNA library, and identified the protein ENIGMA as an HDAC4 binding partner. Further studies showed that other PDZ and LIM proteins do not bind class IIa HDACs, and that ENIGMA can bind class I HDACs with its PDZ domain and class IIa HDACs with its 3LIM domain. These novel preliminary results give rise to our main hypothesis that Enigma is a protein scaffold anchoring class I HDACs to class IIa HDACs to create a complex with high deacetylase activity that represses cardiac hypertrophy.A combination of detailed studies will be conducted to gain an understanding of the composition of this protein complex and its biological role. Specifically, I propose to (1) map the interactions between class IIa HDACs and ENIGMA in detail; (2) determine the endogenous class I HDACs-ENIGMA-Class IIa HDACs' ternary complex; and (3) determine the role of the ENIGMA complex in suppressing hypertrophy in vivo.Multidisciplinary approaches will be used to examine this hypothesis. Biochemical and molecular biology methods, as well as yeast assays, will be used to assess the interaction between ENIGMA and the HDACs. Further cell biology studies will examine the biological role of the ENIGMA ternary complex in cardiomyocytes in primary cultures, using a novel tissue engineered cardiac construct, and using a gene targeted mouse model. These studies will provide important insights into the mechanisms of cardiac hypertrophy."

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