Histone deacetylase inhibitor trichostatin A affects T. cruzi epimastigote stage growth rate.

MEYER CG; TORRES HN; FLAWIÁ MM; ALONSO GD

Mar del Plata. Buenos Aires, Argentina.

Congreso; XLIII Reunión Anual de la Sociedad Argentina de Investigación Bioquímica y Biología Molecular.; 2007

Regulation of gene expression in higher eukaryotes is closely related to post‑translational modification of histones bound to DNA. Lysine residues of the N-terminal tails of histones are acetylated by histone acetyltransferases (HATs) and deacetylated by histone deacetylases (HDACs). We have previously reported the cloning and expression in E. coli of two Trypanosoma cruzi sequences with HAT identity named TcHAT1 and TcElp3. Expression in epimastigotes was confirmed by Northern blot but no HAT activity could be measured to date. In this work we used different approaches to further characterize these enzymes. TcElp3 was cloned into pYES2 and used to transform an Elp3 deficient yeast strain. The transformed cells were not able to rescue the thermosensitive phenotype. We also analyzed expression and localization of TcHAT1 and TcElp3 using specific antibodies obtained after immunization of mice with the recombinant proteins. Subsequently we analyzed the effect of HDACs inhibitors Trichostatin A (TSA) and sodium butyrate in epimastigotes grown in vitro. When parasites were treated with 50 nM TSA strong proliferation inhibition was observed but also a sub G1 peak appeared on DNA histogram when flow cytometry was performed. This evidence not only supports a functional mechanism of histone acetylation in Trypanosoma cruzi but also opens new insights in drug therapy against Chagas’ disease.