Aging promotes reactivation of the Barr body at distal chromosome regions [RNA Major cardiac cell types]

Decades ago, evidence of age-related reactivation of a single gene on the female inactive X chromosome was observed in mice. While stable silencing of the Barr body is crucial for balancing gene dosage between sexes, it remained unclear whether silencing is maintained during aging. Here, we employed allele-specific multi-omics approaches to capture a comprehensive catalog of genes escaping X chromosome inactivation throughout mouse development and aging. We found substantially elevated escape rates during aging across organs, occurring in multiple distinct cell types and concentrated at distal chromosome regions. Consistently, chromatin accessibility was increased across multiple megabases at chromosome ends, affecting regulatory elements of escapees. Since several age-specific escapees are linked to human diseases, their elevated expression in females might contribute to sex-biased disease progression observed during aging. Overall design: RNA-seq from major cardiac cell types (cardiac fibroblasts, cardiomyocytes, endothelial cells, and macrophages) of 9-week-old C57BL/6J?XistxCAST/EiJ mice