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Inhibition of the interaction between class IIA histone deacetylases and myocyte enhancer factor 2 by small molecules

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Title	Inhibition of the interaction between class IIA histone deacetylases and myocyte enhancer factor 2 by small molecules
Author	Jayathilaka, Nimanthi
Author email	jayathil@usc.edu;njayathi@gmail.com
Degree	Doctor of Philosophy
Document type	Dissertation
Degree program	Genetic, Molecular and Cellular Biology
School	Keck School of Medicine
Date defended/completed	2011-06-27
Date submitted	2011-08-03
Date approved	2011-08-03
Restricted until	2012-08-03
Date published	2012-08-03
Advisor (committee chair)	Chen, Lin
Advisor (committee member)	Chen, Xiaojiang Roberts, Richard
Abstract	Enzymes that modify epigenetic status provide attractive targets for therapy in various diseases including cardiac hypertrophy, cancer, neurodegenerative diseases, and immune dysfunction. The therapeutic development of epigenetic modulators, however, has been largely limited to direct targeting of the active site of such enzymes. Class IIa histone deacetylases (HDACs) are a group of epigenetic enzymes that depends on interaction with Myocyte Enhancer Factor-2 (MEF2) for their recruitment to specific genomic loci. Targeting this interaction presents a potential alternative approach to inhibiting this class of HDACs by blocking their DNA recruitment. In this paper, we have identified and characterized a group of small molecules that indirectly target class IIa HDACs by binding to MEF2. ❧ The first study explores the molecular interactions between the MEF2 family and the class IIa HDACs. This study revealed that the interfaces between the class IIa HDACs and the MEF2 proteins are sensitive to localized mutations and, therefore, likely targets for inhibition by small molecules. Moreover, we established a mammalian two-hybrid assay that can serve as a screen for small molecule inhibitors of MEF2:HDAC4 interaction. ❧ The second study establishes that the commercially available small molecule, BML-210, which belongs to the pimeloylanilide o-aminoanilide (PAOA) class, is an inhibitor of MEF2:HDAC4 interaction in vitro and in vivo. Specifically, we showed that these small molecules blocked the recruitment of class IIa HDACs to MEF2-targeted genes and enhanced the expression of those targets. Based on structural and functional studies, we synthesized a series of new PAOA compounds, some of which were more potent inhibitors of MEF2:HDAC interaction. ❧ The final study examines the effect of these MEF2:class IIa HDAC inhibitors on learning and memory. In this blind study, we showed that wild type (WT) mice treated with a PAOA molecule displayed enhanced learning and memory compared to mice treated with an inactive PAOA compound. Furthermore, in a similar study, treatment of cultured cortical neurons with PAOA led to a significant decrease in the excitatory synapse number, suggesting, that the effect of PAOA on learning and memory might be through regulating synapse formation. These findings link the inhibition of MEF2:HDAC interaction to MEF2 dependent synaptic morphogenesis, learning and memory. ❧ Collectively, our work describes the first example of sub-class specific HDAC inhibitors (HDACi) that disrupt the protein-protein interaction between the class IIa HDACs and its cofactors. In addition, as evident from the final functional study on the effect of these compounds on synapse formation and memory, the compounds developed here can be used not only as tools to study the MEF2 proteins and class IIa HDACs in vivo but also as leads for drug development.
Keyword	histone deacetylases (HDAC); HDAC inhibitors; myocyte enhancer factor 2 (MEF2); transcription regulation
Language	English
Part of collection	University of Southern California dissertations and theses
Publisher (of the original version)	University of Southern California
Place of publication (of the original version)	Los Angeles, California
Publisher (of the digital version)	University of Southern California. Libraries
Provenance	Electronically uploaded by the author
Type	texts
Legacy record ID	usctheses-m
Rights	Jayathilaka, Nimanthi
Access conditions	The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given.
Repository name	University of Southern California Digital Library
Repository address	USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA
Repository email	cisadmin@usc.edu
Archival file	uscthesesreloadpub_Volume71/etd-Jayathilak-246.pdf