Inhibition of the function of class IIa HDACs by blocking their interaction with MEF2

Nimanthi Jayathilaka, Aidong Han, Kevin J. Gaffney, Raja Dey, Jamie A. Jarusiewicz, Kaori Noridomi, Michael A. Philips, Xiao Lei, Ju He, Jun Ye, Tao Gao, Nicos A. Petasis, Lin Chen

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Enzymes that modify the epigenetic status of cells provide attractive targets for therapy in various diseases. The therapeutic development of epigenetic modulators, however, has been largely limited to direct targeting of catalytic active site conserved across multiple members of an enzyme family, which complicates mechanistic studies and drug development. 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 an alternative approach to inhibiting this class of HDACs. Wehave used structural and functional approaches to identify and characterize a group of small molecules that indirectly target class IIa HDACs by blocking their interaction with MEF2 on DNA. We used X-ray crystallography and 19FNMR to show that these compounds directly bind to MEF2. We have also shown that the small molecules blocked the recruitment of class IIa HDACs to MEF2-targeted genes to enhance the expression of those targets. These compounds can be used as tools to study MEF2 and class IIa HDACs in vivo and as leads for drug development.

Original languageEnglish (US)
Pages (from-to)5378-5388
Number of pages11
JournalNucleic acids research
Volume40
Issue number12
DOIs
StatePublished - Jul 1 2012

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MEF2 Transcription Factors
Histone Deacetylases
Epigenomics
Catalytic Domain
Enzymes
X Ray Crystallography
Pharmaceutical Preparations
Inhibition (Psychology)
DNA
Therapeutics
Genes

Cite this

Jayathilaka, N., Han, A., Gaffney, K. J., Dey, R., Jarusiewicz, J. A., Noridomi, K., ... Chen, L. (2012). Inhibition of the function of class IIa HDACs by blocking their interaction with MEF2. Nucleic acids research, 40(12), 5378-5388. https://doi.org/10.1093/nar/gks189

Inhibition of the function of class IIa HDACs by blocking their interaction with MEF2. / Jayathilaka, Nimanthi; Han, Aidong; Gaffney, Kevin J.; Dey, Raja; Jarusiewicz, Jamie A.; Noridomi, Kaori; Philips, Michael A.; Lei, Xiao; He, Ju; Ye, Jun; Gao, Tao; Petasis, Nicos A.; Chen, Lin.

In: Nucleic acids research, Vol. 40, No. 12, 01.07.2012, p. 5378-5388.

Research output: Contribution to journalArticle

Jayathilaka, N, Han, A, Gaffney, KJ, Dey, R, Jarusiewicz, JA, Noridomi, K, Philips, MA, Lei, X, He, J, Ye, J, Gao, T, Petasis, NA & Chen, L 2012, 'Inhibition of the function of class IIa HDACs by blocking their interaction with MEF2', Nucleic acids research, vol. 40, no. 12, pp. 5378-5388. https://doi.org/10.1093/nar/gks189
Jayathilaka N, Han A, Gaffney KJ, Dey R, Jarusiewicz JA, Noridomi K et al. Inhibition of the function of class IIa HDACs by blocking their interaction with MEF2. Nucleic acids research. 2012 Jul 1;40(12):5378-5388. https://doi.org/10.1093/nar/gks189
Jayathilaka, Nimanthi ; Han, Aidong ; Gaffney, Kevin J. ; Dey, Raja ; Jarusiewicz, Jamie A. ; Noridomi, Kaori ; Philips, Michael A. ; Lei, Xiao ; He, Ju ; Ye, Jun ; Gao, Tao ; Petasis, Nicos A. ; Chen, Lin. / Inhibition of the function of class IIa HDACs by blocking their interaction with MEF2. In: Nucleic acids research. 2012 ; Vol. 40, No. 12. pp. 5378-5388.
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