A Histone Methyltransferase Modulates Antigenic Variation in African Trypanosomes

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Abstract
To evade the host immune system, several pathogens periodically change their cell-surface epitopes. In the African trypanosomes, antigenic variation is achieved by tightly regulating the expression of a multigene family encoding a large repertoire of variant surface glycoproteins (VSGs). Immune evasion relies on two important features: exposing a single type of VSG at the cell surface and periodically and very rapidly switching the expressed VSG. Transcriptional switching between resident telomeric VSG genes does not involve DNA rearrangements, and regulation is probably epigenetic. The histone methyltransferase DOT1B is a nonessential protein that trimethylates lysine 76 of histone H3 in Trypanosoma brucei. Here we report that transcriptionally silent telomeric VSGs become partially derepressed when DOT1B is deleted, whereas nontelomeric loci are unaffected. DOT1B also is involved in the kinetics of VSG switching: in ΔDOT1B cells, the transcriptional switch is so slow that cells expressing two VSGs persist for several weeks, indicating that monoallelic transcription is compromised. We conclude that DOT1B is required to maintain strict VSG silencing and to ensure rapid transcriptional VSG switching, demonstrating that epigenetics plays an important role in regulating antigenic variation in T. brucei. The surface of Trypanosoma brucei, a unicellular parasite that lives in the bloodstream of its mammalian host, is coated with glycoprotein (VSG) molecules. To evade elimination by the immune system, this parasite replaces its coat with one tailored from another glycoprotein variant. Even though there are hundreds of VSG genes in the genome, this process, called antigenic variation, works because all are silenced except for the one that encodes the current coat. In this work, we show that the chromatin-modifying enzyme DOT1B helps to epigenetically regulate the number of VSGs each parasite can have at a time at the surface and how fast each parasite can switch from one coat to another. In parasites lacking DOT1B, silent VSG genes become partially active and the switch from one VSG to another slows down, allowing two different VSGs to appear on the surface of an individual parasite at the same time. Our studies reveal the importance of epigenetics in regulating VSG genes and provide new insights toward the understanding of this unique survival device.