Epigenetic regulation of transcription and virulence in Trypanosoma cruzi by O-linked thymidine glucosylation of DNA
Ekanayake, Dilrukshi Kumari
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In trypanosomes, unlike most eukaryotes, genes transcribed by RNA polymerase II (Pol II) are arranged in polycistronic transcription units (PTUs). Based on this organization, it has been held that trypanosomes rely solely on post-transcriptional processes to regulate gene expression. However, very little is known about how transcription is regulated in trypanosomes. Here, we have characterized the function of a novel glucosylated thymidine DNA residue (base J) in Trypanosoma cruzi. We found that base J localizes to promoter regions of PTUs throughout the T. cruzi genome. Loss of base J following genomic deletion of the thymidine hydroxylase involved in J synthesis (JBP1) led to a global increase in RNA polymerase II transcription and gene expression. We characterized changes in chromatin structure following base J depletion, and observed that loss of base J coincides with decreased nucleosome occupancy, increased histone acetylation, and increased RNA polymerase II occupancy at promoter regions. Changes in gene expression due to loss of base J may increase the ability of T. cruzi to invade mammalian cells and decrease its capacity to egress from host cells in vitro. These studies present the first detailed analysis of the role of base J in chromatin structure and regulation of Pol II-dependent transcription in kinetoplastids.