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The Trypanosomatidae family includes pathogenic species of medical and veterinary interest. Chagas disease is endemic in Latin America, and about 8 million people are infected worldwide. There is a need for more effective drugs for the acute, undetermined and chronic phases of the disease that, in addition, do not cause side effects, stimulating the search for identification of new drug targets, as well as new chemotherapeutic targets. Trypanosomatids contain characteristic structures, such as the nucleus that undergoes a closed mitosis without chromosome formation and variations of chromatin packing in the different protozoa developmental stages. The nuclear DNA is condensed by histones that suffer post-translational modifications, such as addition of methyl groups by histone methyltransferases (MHT) and addition of acetyl groups by acetyltransferases. These processes modulate gene expression and chromatin organization, which are crucial to transcription, replication, repair and recombination. In the present study, the effects of chaetocin, a HMT inhibitor, on T. cruzi epimastigote proliferation, viability, ultrastructure and cell cycle were investigated. Results indicate that chaetocin promoted irreversible inhibition of protozoa growth, evident unpacking of nuclear heterochromatin and intense nucleolus fragmentation, which is associated with parasite cell cycle arrest and RNA transcription blockage. Taken together, data obtained with chaetocin treatment stimulate the use of histone methyltransferase inhibitors against pathogenic trypanosomatids., (Copyright © 2017 Elsevier B.V. All rights reserved.)