Inositol phosphate pathway controls transcription of telomeric expression sites in trypanosomes

African trypanosomes cause human and animal diseases and evade the host immune systems by periodically switching which variant surface glycoprotein (VSG) they express. The mechanisms that result in expression of one of the numerous VSG genes at a time and the switching of expression between different VSG genes are poorly understood. We show that specific steps in the inositol phosphate (IP) pathway control both monoallelic VSG gene transcription and the switching of VSG gene expression. The data indicate that the cellular amounts, locations, and molecular interactions of specific IP pathway enzymes and their metabolites control both processes. The results offer new drug targets and insights into the epigenetic control of gene expression by this biologically ubiquitous pathway.