title: 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 in large polycistronic gene clusters transcribed by polymerase II (Pol II). Thus, it is thought that trypanosomes rely solely on posttranscriptional processes to regulate gene expression. Here, we show that the glucosylated thymine DNA base (β-d-glucosyl-hydroxymethyluracil or base J) is present within sequences flanking the polycistronic units (PTUs) in T. cruzi. The loss of base J at sites of transcription initiation, via deletion of the two enzymes that regulate base J synthesis (JBP1 and JBP2), correlates with an increased rate of Pol II transcription and subsequent genome-wide increase in gene expression. The affected genes include virulence genes, and the resulting parasites are defective in host cell invasion and egress. These studies indicate that base J is an epigenetic factor regulating Pol II transcription initiation in kinetoplastids and provides the first biological role of the only hypermodified DNA base in eukaryotes.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Georgia, 120 Green Street, Life Sciences Building, Athens, GA 30602-7229, USA.
authors.forename: Dilrukshi K
authors.initials: DK
authors.lastname: Ekanayake
authors.forename: Todd
authors.initials: T
authors.lastname: Minning
authors.forename: Brent
authors.initials: B
authors.lastname: Weatherly
authors.forename: Kapila
authors.initials: K
authors.lastname: Gunasekera
authors.forename: Daniel
authors.initials: D
authors.lastname: Nilsson
authors.forename: Rick
authors.initials: R
authors.lastname: Tarleton
authors.forename: Torsten
authors.initials: T
authors.lastname: Ochsenreiter
authors.forename: Robert
authors.initials: R
authors.lastname: Sabatini
mesh_terms: D016054:DNA, Protozoan / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D006031:Glycosylation; D020411:Oligonucleotide Array Sequence Analysis; D013941:Thymine / Q000378:metabolism*; D014158:Transcription, Genetic; D014349:Trypanosoma cruzi / Q000201:enzymology / Q000235:genetics* / Q000472:pathogenicity*; D014774:Virulence
chemical_list: D016054:DNA, Protozoan; D013941:Thymine