HISTONEH1TRYP · Chromatin and antigenic variation: The role of histone H1 in gene regulation in African trypanosomes

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

African trypanosomes developed a remarkable strategy to escape the immune system of its mammalian host. The bloodstream forms of the parasite express only one type of variant surface glycoprotein (VSG) at the surface. Only one VSG gene is active at a time, among a repertoire of thousands of genes. T. brucei switches periodically the active VSG gene maintaining the other VSG genes silenced, which gives rise to an efficient mechanism of antigenic variation. The active VSG is expressed from a specific subtelomeric region called the expression site (ES). Although there are 15 ESs in the genome, only one is active at any given time. The mechanism behind monoallelic VSG expression is still elusive but several chromatin factors like chromatin remodellers and histone-modifying proteins have been recently implicated. Importantly, active and silent ESs show different chromatin structures: active ES display a more decondensed chromatin, depleted of nucleosomes, whereas silent ESs have a nucleosome-richer, condensed chromatin [1,2]. Histone H1 links the DNA entering and exiting the nucleosomes, the basic units of chromatin, being crucial to establish and maintain higher-order chromatin structures. Contrary to the long established idea that histone H1 was a general repressor of chromatin, it has been recognized that histone H1 can negatively or positively regulate specific genes in several eukaryotes. Also, there is increasing reports of histone H1 class-specific functions [3]. In T. brucei histone H1 was shown to induce chromatin condensation in vitro [4]. In this project, we studied the role played by histone H1 in antigenic variation, and gene regulation in general. We showed that: • H1 is dispensable for parasite growth in culture • H1 compacts chromatin at different levels across the genome • H1 regulates expression of Pol I-transcribed genes • H1 inhibits transcription from silent BESs and procyclin sites • Loss of H1 increases resistance to MMS-induced DNA damage • H1 is important for parasite fitness in vivo These results are described in a manuscript that is currently under review in Molecular Microbiology journal. We are currently investigating the distribution of histone H1 along the genome, as well as its putative role in splicing. Histone H1 is an important component of chromatin in T. brucei. It regulates not only VSG genes, but also all other Pol I transcribed genes. Given there are many genes encoding for Histone H1 in higher eukaryotes, it has been difficult to study this key chromatin component in these organisms. Our findings have revealed novel functions of histone H1, which has great significance to the broader chromatin biology field. [1] Figueiredo, L. M. and Cross, G. A. M. (2010). Nucleosomes are depleted at the VSG expression site transcribed by RNA polymerase I in African trypanosomes. Eukaryot. Cell 9:148-154. [2] Stanne, T.M. and Rudenko, G. (2010). Active VSG expression sites in Trypanosoma brucei are depleted of nucleosomes. Eukaryot. Cell 9:136-147. [3] Izzo, A. et al. (2008). The histone H1 family: specific members, specific functions? Biol. Chem. 389:333-43. [4] Burri, M. et al. (1995). Partial amino acid sequence and functional aspects of histone H1 proteins in Trypanosoma brucei brucei. Biol.Cell. 83:23-31.

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