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Distinct histone modification profiles at transcription start sites during development of the parasite Trypanosoma cruzi.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. (Lena Åslund)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. (Lena Åslund)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
(English)Manuscript (Other academic)
Abstract [en]

The parasite Trypanosoma cruzi is the etiological agent causing Chagas' disease in Central and South America. This protozoon presents a complex life cycle that comprises three major developmental stages as the parasite is transmitted from the invertebrate vector to a mammalian host. Such drastic environmental changes demand rapid adjustment of the parasite cellular processes. This adaptation appears to be mainly achieved by regulating gene expression levels through post-transcriptional processes. We have previously shown the important role of chromatin in regulating transcriptional initiation through histone modifications. Histones typically associated with active chromatin states (i.e. histone acetylation and histone H3 trimethylated K4) were preferentially enriched at sequences directly flanking transcription start sites in the intergenic region between divergently transcribed polycistronic gene clusters. In this study, we compare acetylated histone H3 profiles in replicative (i.e. logarithmic epimastigotes) and non-replicative (i.e. stationary epimastigotes and trypomastigotes) parasite stages. Histone acetylation was found less abundant in non-replicative stages consistent with previous observations of diminished transcriptional activity in these stages and suggesting potential links between transcription and replication. This was also accompanied by possible changes in nucleosome positioning. We also report the epigenetic profile of histone H3 trimethylated K36, a histone modification previously uncharacterized in T. cruzi . This histone mark was found enriched at regions of transcriptional initiation, suggesting a rather distinct function compared with its established roles in other organisms.

Keyword [en]
Trypanosoma cruzi; histone modifications; bidirectional transcription
URN: urn:nbn:se:uu:diva-100264OAI: oai:DiVA.org:uu-100264DiVA: diva2:210555
Available from: 2009-04-02 Created: 2009-03-29 Last updated: 2010-01-14
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.
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
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)
Available from: 2009-04-23 Created: 2009-03-29 Last updated: 2010-02-22Bibliographically approved

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