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Histone acetylation and methylation at sites initiating divergent polycistronic transcription in Trypanosoma cruzi
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. (Lena Åslund)
Program for Genomics and Bioinformatics, Department of Cell and Molecular Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden. (Björn Andersson)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. (Claes Wadelius)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
2008 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, Vol. 283, no 23, 15884-15892 p.Article in journal (Refereed) Published
Abstract [en]

Trypanosomes are ancient eukaryotic parasites in which the protein-coding genes, organized in large polycistronic clusters on both strands, are transcribed from as yet unidentified promoters. In an effort to reveal transcriptional initiation sites, we examined the Trypanosoma cruzi genome for histone modification patterns shown to be linked to active genes in various organisms. Here, we show that acetylated and methylated histones were found to be enriched at strand switch regions of divergent gene arrays, not at convergent clusters or intra- and intergenic regions within clusters. The modified region showed a bimodular profile with two peaks centered over the 5'-regions of the gene pair flanking the strand switch region. This pattern, which demarcates polycistronic transcription units originating from bidirectional initiation sites, is likely to be common in kinetoplastid parasites as well as in other organisms with polycistronic transcription. In contrast, no acetylation was found at promoters of the highly expressed rRNA and spliced leader genes or satellite DNA or at tested retrotransposonal elements. These results reveal, for the first time, the presence of specific epigenetic marks in T. cruzi with potential implications for transcriptional regulation; they indicate that both histone modifications and bidirectional transcription are evolutionarily conserved.

Place, publisher, year, edition, pages
2008. Vol. 283, no 23, 15884-15892 p.
Keyword [en]
Trypanosoma cruzi, histones, transcription, strand-switch regions
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-99850DOI: 10.1074/jbc.M802081200ISI: 000256332500047PubMedID: 18400752OAI: oai:DiVA.org:uu-99850DiVA: diva2:210554
Available from: 2009-04-02 Created: 2009-03-20 Last updated: 2009-11-03Bibliographically approved
In thesis
1. Gene Regulation and Epigenetic Mechanisms in the Parasite Trypanosoma cruzi
Open this publication in new window or tab >>Gene Regulation and Epigenetic Mechanisms in the Parasite Trypanosoma cruzi
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Trypanosomes are unicellular protozoan parasites responsible for several human diseases that affect millions of people and cause thousands of casualties every year. They also represent a primitive eukaryotic model system harboring unique processes and basic regulatory mechanisms such as RNA-editing, polycistronic transcription and trans-splicing, first described in these organisms. Unlike most eukaryotes where levels of gene expression are controlled at initiation of transcription, trypanosomes use post-transcriptional events as the main regulators. This thesis explores the epigenetic mechanisms involved in gene expression control in trypanosomes, providing the first evidences for a functional “histone-code” as well as the existence and location of DNA methylation in Trypanosoma cruzi.

Chromatin immunoprecipitation (ChIP) was used for the profiling of acetylated and methylated histones in T. cruzi, showing that the modified histones were exclusively localized at bidirectional transcription start sites. In addition, promoters from highly transcribed genes were found depleted of nucleosomes, while DNA regions expected to be silent were not enriched in the investigated modified histones. Furthermore, we showed that the histone patterns were developmentally regulated.

The first in depth characterization of the DNA methylation patterns in T. cruzi was presented in this work. We detected m5C in regions of transcriptional initiation and termination, retrotransposons, pseudogenes and the kinetoplast minicircle. We also showed that the amount of methylation changes during development, with an increase in non-replicative forms.

We also characterized the DNA-interacting properties of a T. cruzi polypyrimidine-tract binding protein (TcPTB), and its potential role as a transcription factor. TcPTB was found to interact with single-stranded DNA present in promoters bound by its mammalian homologue as well as to the region of transcriptional initiation in Leishmania major. We also demonstrated that T. cruzi polypyrimidine stretches were able to confer ssDNA conformations.

Overall, these results provide new insights into the biology of ancient pathogenic parasites, which might be exploited for drug development.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 55 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 446
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:uu:diva-100265 (URN)978-91-554-7490-4 (ISBN)
Public defence
2009-05-14, Rudbeck Hall, Rudbeck Laboratory, Dag Hammarskjölds väg 20, Uppsala, 14:15 (English)
Opponent
Supervisors
Available from: 2009-04-23 Created: 2009-03-29 Last updated: 2010-02-22Bibliographically approved

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