Researchers show that an intracellular metabolite of glutamine, alpha-ketoglutarate, plays a role in regulating cellular differentiation programs by changing the DNA-binding patterns of the transcription factor CTCF and by altering genome interactions. As an added level of gene program control complexity, they have found that the genome’s context near the binding sites — such as epigenetic changes or altered genome topology — affects whether the binding turns on or turns off gene programs.