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Epigenetic regulation of transcription and virulence in Trypanosoma cruzi by O-linked thymine glucosylation of DNA

ABSTRACT: Unlike other eukaryotes, the protein coding genes of Trypanosoma cruzi are arranged into large polycistronic gene clusters transcribed by polymerase II (Pol II). Thus, trypanosomes rely on post-transcriptional processes to regulate gene expression. Here, we show that the glucosylated thymine DNA base (-D-glucosyl hydroxymethyluracil or base J) is present within sequences flanking the polycistronic units (PTU) in T. cruzi. loss of base J at sites of transcription initiation, via deletion of the two enzymes that regulate J synthesis (JBP1 and JBP2), correlates with an increased rate of Pol II transcription and subsequent genome-wide increase in gene expression. genes include virulence genes and the resulting parasites are defective in host cell invasion and egress. These studies indicate that base J represents an epigenetic factor regulating Pol II transcription initiation in kinetoplastids, and provides the first biological role of the only hyper-modified DNA base in eukaryotes. This entry contains the results using SLT, digital gene expression profiling of tags read off the spliced leader sequence of all mature trypanosomatid messages, for the life-cycle of T. cruzi, four stages, in wild-type as well as JBP1 KO cells.

ORGANISM(S): Trypanosoma cruzi

PROVIDER: GSE26754 | GEO | 2011/01/21

SECONDARY ACCESSION(S): PRJNA136343

REPOSITORIES: GEO

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Epigenetic regulation of transcription and virulence of Trypanosoma cruzi

Project description:Trypanosoma cruzi, a flagellated protozoan, is the causative agent of Chagas’ disease, a chronic and potentially fatal disease that causes irreversible damage to heart and digestive tract in humans. Like all trypanosomes, the protein coding genes of T. cruzi are arranged into large polycistronic gene clusters transcribed by polymerase II (Pol II). Therefore, trypanosomes presumably rely on post-transcriptional process to regulate gene expression. Pol II promoters have not been identified and there is no evidence for regulated gene expression at the transcriptional level. However, the presence of the hyper-modified DNA base J, Beta-D-glucosyl hydroxymethyluracil, at regions flanking the polycistronic units (PTU) in T. brucei suggested its involvement in regulating Pol II transcription. We now demonstrate that base J is localized at PTU flanking regions in T. cruzi and levels are differentially regulated by the thymidine hydroxylases, JBP1 and JBP2, involved in J biosynthesis. Microarray analysis of the JBP1dKO and JBP2dKO indicate the up and down regulation of several hundred genes distributed throughout the genome. We show a large increase in Pol II transcription rate following the decrease in base J at the PTU flanks. Changes in gene expression include virulence genes and parasites are defective in host cell invasion and egress. There is a direct correlation between the reduction in base J levels, number of genes affected and strength of the virulence phenotype. These studies indicate that base J represents an epigenetic factor regulating Pol II transcription initiation in kinetoplastids and provides a biological role of the only hyper-modified DNA base in eukaryotes. J1 and J2 null mutant trypomastigotes were each compared to wild type trypomastigotes. There were 3 biological replicates for each comparison.

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