Aging promotes escape from X chromosome inactivation in human tissues

Abstract

Age-related diseases often show sex differences, yet their molecular bases remain unclear. Mouse models suggest that aging disrupts X chromosome inactivation (XCI) in females. Here, we test whether this phenomenon extends to humans by analyzing allele-specific gene expression derived from: i) bulk RNAseq data from three females with non-mosaic XCI; and ii) single cell RNAseq data from the immune cells of hundreds of females. We find that age-dependent escape from XCI also occurs in human females, particularly among: i) genes at the distal (Xq) end of the X chromosome; and ii) those involved in sister chromatid cohesion, gene regulation, and glutamate signaling. These findings implicate reactivation of the inactive X in human female-specific aging processes and highlight potential mechanisms underlying sex-biased outcomes in age-related diseases.