Objective
Trypanosoma brucei is a unicellular parasite that causes African sleeping sickness, a fatal disease in humans. There is no vaccine and drugs are very scarce and toxic. T. brucei evades the host immune system by periodically changing its dense, uniform coat of variant surface glycoproteins (VSGs), a mechanism knows as antigenic variation. There are hundreds of VSG genes in the genome, but only one is transcriptionally active at a time. I recently observed major structural differences between the chromatin of active and silent VSGs, with the active VSG essentially being devoid of regularly spaced nucleosomes. The factors involved in establishing and maintaining such disparate chromatin conformations remain unknown. In other eukaryotes, much has been learned about the role of canonical histones in gene regulation, but the role of the linker histone H1 remains elusive. Here I propose to characterize histone H1 in T. brucei, specifically investigating its role in VSG regulation. T. brucei has six different H1 isotypes, which can be grouped into three classes based on their N-terminal sequences. Each class will be epitope-tagged so that their nuclear localization can be compared and the genome-wide distribution of each class can be determined. RNA interference will be used to deplete either all or class-specific H1 and the phenotypes will be examined in two ways: by testing the effects on overall chromatin organization and by testing the specific effects on the VSG gene family, including transcriptional regulation, chromatin structure and switching. Finally, bulk or individual H1 proteins will be purified in order to map the post-translational modifications of H1, and amino acid mutagenesis will subsequently be used to test the role(s) of a subset of these modifications. In this study, I hope to participate in the current effort to put histone H1 “back on the map,” while at the same time seeking to understand the role of chromatin in antigenic variation.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
- medical and health sciences clinical medicine psychiatry sleep disorders
- natural sciences biological sciences biochemistry biomolecules proteins
- natural sciences biological sciences genetics RNA
- natural sciences chemical sciences organic chemistry amines
- natural sciences biological sciences genetics genomes
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Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Call for proposal
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
FP7-PEOPLE-2009-RG
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Funding Scheme
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Coordinator
1649 028 Lisboa
Portugal
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