Is (HAT) [17]. Upon initial human infection, T. brucei invades interstitial spaces, the lymph system, and the bloodstream. With prolonged infection, the parasite crosses the blood rain barrier and invades the central nervous system [18]. Without treatment HAT is often fatal and although the number of cases is declining, more than 1.8 million people are still thought to be at high risk of the disease [19]. As the parasite cycles between the mammalian host and the insect vector, it differentiates into different life cycle stages including the bloodstream form (BF) in the mammal or the procyclic form (PF) in the midgut of the tsetse fly [20]. In the bloodstream of the mammalian host, T. brucei escapes clearance by the immune system by periodically switching a mono-allelically expressed variant surface glycoprotein (VSG), an abundant cell surface protein that masks invariant cell surface proteins [21, 22]. The active VSG is expressed from a single pol I-transcribedsubtelomeric VSG expression site (ES) [23]. The expressed VSG gene can be switched through multiple mechanisms [24]. First of all, a transcriptional switch can result in silencing of the active ES and the activation of one of approximately 15 other silent ESs. Alternatively, DNA recombination can be involved. Gene conversion can result in all or part of the active VSG gene being swapped with sequences from a different silent VSG cassette, present on a variety of types of chromosomes. T. brucei contains 11 megabase chromosomes (>1 Mb), 5 intermediate chromosomes (200?00 kb), and 100 mini-chromosomes (30?50 kb), and all of these contain silent VSGs [25]. Lastly, VSGs can be switched through telomere exchange with another VSG-containing telomere. ESs are telomeric transcription units. There is a relatively localized telomeric silencing gradient extending up to 10 kb from the telomere end, although this is not implicated in the ES regulation involved in antigenic variation [26?9]. The telomeric repression observed in the immediate vicinity of the telomeres of the silent ESs appears superficially reminiscent of that observed in yeast and Drosophila in that it requires RAP1, among other factors [26]. However, SIR2, which plays an important role in telomere position effect in eukaryotes, appears to also have Pedalitin permethyl ether site unrelated functions in T. brucei [29]. Additional repressive mechanisms appear to operate on the ES promoter itself. These is about 40?0-kb upstream from the chromosome end and is effectively silenced, even though distance-wise it would be expected to escape the effects of typical telomere position effect [30]. A number of proteins including the chromatin remodelers ISWI [31, 32], ORC1 PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/26100631 [33], FACT [34], and HDAC3 [35] among others, play a role in ES promoter silencing. In addition, T. brucei histone H1, similar to the C-terminal tail of the H1 from metazoans, renders chromatin in the BF stage more resistant to nucleases, presumably due to a more closed chromatin conformation. H1 is also required for full transcriptional repression of silent ESs [36, 37]. Another unusual feature of ESs is that they are transcribed in a mono-allelic fashion by pol I, which in eukaryotes normally exclusively transcribes ribosomal DNA (rRNA) [38]. Unusually for a eukaryote, protein-coding genes in T. brucei are arranged in extensive, polycistronic transcription units (PTUs). These are constitutively transcribed by pol II from poorly defined promoters and can span up to several hundred kilobases [39].