Epigenetics and Transcription in Leishmania

Faculty Lead(s)

Peter Myler

Keywords

Bioinformatics
Genomics
Parasite Molecular Biology

Project Summary

The very first cosmid clone from the Leishmania major genome that we sequenced at Seattle Biomed in 1997 offered insight into the unusual gene organization of trypanosomatid genomes – it contained a divergent strand-switch region (as it turned out, the only one on all of chromosome 1). Over the next 10 years, my laboratory was at the forefront in defining the genomic elements and chromatin modifications involved in transcription initiation in Leishmania, as well as defining many of the protein components of the RNA polymerase II and III initiation and elongation complexes. After a brief hiatus in the late 2000s, these activities have been re-kindled by my involvement (in collaboration with the Borst group in Amsterdam) in showing that the trypanosomatid-specific modified DNA base J plays an important role in transcription termination in Leishmania. I am now PI on an NIAID grant investigating the sequence elements and protein machinery involved J insertion and maintenance, as well as the molecular mechanism(s) underlying its involvement in transcription termination.

  1. Martínez-Calvillo S, Yan S, Nguyen D, Fox M, Stuart K, Myler PJ. (2003) Transcription of Leishmania major Friedlin chromosome 1 initiates in both directions within a single region. Mol Cell, 11:1291-9. PubMed: 12769852.
  2. van Luenen HG, Farris C, Jan S, Genest PA, Tripathi P, Velds A, Kerkhoven RM, Nieuwland M, Haydock A, Ramasamy G, Vainio S, Heidebrecht T, Perrakis A, Pagie L, van Steensel B, Myler PJ, Borst P. (2012) Glucosylated hydroxymethyluracil, DNA base J, prevents transcriptional readthrough in Leishmania. Cell, 150:909-21. PubMed: 22939620; PubMed Central: PMC3684241.
  3. Sekar A, Merritt C, Baugh L, Stuart K, Myler PJ. (2014) 10.6900 encodes the glucosyltransferase involved in synthesis of base J in Trypanosoma brucei. Mol Biochem Parasitol, 196:9-11. PubMed: 25064607; PubMed Central: PMC4206709
  4. Genest PA, Baugh L, Taipale A, Zhao W, Jan S, van Luenen HG, Korlach J, Clark T, Luong K, Boitano M, Turner S, Myler PJ, Borst P. (2015) Defining the sequence requirements for the positioning of base J in DNA using SMRT sequencing. Nucl Acids Res, 43:2102-15. PubMed: 25662217; PubMed Central: PMC4344527.