HISTONEH1TRYP

Chromatin and antigenic variation: The role of histone H1 in gene regulation in African trypanosomes

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 Obiettivo del progetto (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.'

Introduzione (Teaser)

Trypanosomiasis, also known as African sleeping sickness, is a fatal infection caused by the parasite Trypanosoma brucei. A European study investigated how Trypanosoma brucei evades immune attack.

Descrizione progetto (Article)

Trypanosomes have developed a remarkable strategy for escaping host immune responses by periodically changing the variant surface glycoprotein (VSG) expressed on the surface of the parasite. Although there are hundreds of VSG genes in the genome, the bloodstream form of the parasite expresses only one gene at a time.

Gene expression is tightly linked with chromatin structure and the accessibility of the transcribed regions by various transcription factors. Chromatin remodelling is driven by specialised proteins that modify associated histones. Accumulating evidence indicates that histone H1 can negatively or positively regulate gene transcription.

The scope of the EU-funded 'Chromatin and antigenic variation: The role of histone H1 in gene regulation in African trypanosomes' (HISTONEH1TRYP) project was to elucidate the mechanism behind this VSG monoallelic expression. The work focused on histone H1 and how it controls antigenic variation in T.brucei.

Experimental data indicated that although histone H1 is dispensable for parasite growth in culture, it determines parasite fitness in vivo. Histone H1 works by compacting chromatin at various regions throughout the parasite genome and thereby regulates transcription of various genes including VSG.

Collectively, the findings of the HISTONEH1TRYP project unveil a novel function of histone H1 in the antigenic variation and immune evasion of T.brucei. This information could form the basis for the design of novel therapeutics targeting histone H1 modifications.