The Xist locus on the X chromosome of males regulates cognition and metabolism despite minimal expression

The long non-coding RNA Xist is the master regulator of X chromosome inactivation (XCI) in females, but its functional significance in males, where Xist expression is normally minimal, is unknown. Here we investigated whether the Xist locus influences male physiology and brain function across the lifespan using mice carrying a targeted Xist deletion ({Delta}Xist). Xist deletion produced a small further reduction in the very low, residual Xist signal in aged male hippocampus. Metabolically, Xist deletion lowered fasting blood glucose in old, not young, males, without affecting body weight. In the brain, Xist deletion modestly improved spatial memory at 24 hours in the Morris water maze in young males, with a similar trend at middle age in an interactive place avoidance task, independent of anxiety-like behavior or locomotor activity. This early cognitive benefit did not persist with aging and motor function on the rotarod was unaffected by genotype at any age. Together, these findings indicate that the Xist locus exerts age- and domain-specific effects on male metabolic and cognitive functions despite near-absent baseline Xist expression. These data identify an unexpected role for a canonically female-associated regulatory locus in males and raise the possibility that Xist-associated mechanisms contribute to male brain function and metabolism.