Skewed escape from X-inactivation underlies female bias in Sjögren’s syndrome

Abstract

Many autoimmune diseases feature strikingly increased prevalence in females, such as systemic lupus erythematosus (female-to-male ratio 9:1), systemic sclerosis (female-to-male ratio 11:1) and Sjögren’s syndrome (female-to-male ratio 14:1). However, the molecular basis underlying female-biased autoimmunity remains elusive. To address this knowledge gap, we performed transcriptomic profiling of minor salivary gland-derived mesenchymal stromal cells (MSCs) from primary Sjögren’s syndrome (pSS) patients and control subjects. While autosomal gene expression profiles were largely comparable between pSS and control MSCs, we detected major differences in the regulation of X-linked genes. In control female MSCs, X-linked genes that escaped inactivation were expressed from both parental and maternal X chromosomes with a median paternal ratio of ~0.5. However, in pSS female MSCs, escapees exhibited preferential expression from one of the two X chromosomes. Concomitantly, pSS MSCs showed decrease in XIST levels and reorganization of H3K27me3+ foci in the nucleus, suggesting a global dysregulation of X-inactivation maintenance. The skewing in X escape in pSS MSCs was accompanied by mislocation of protein products encoded by the escapees. Given the hallmark features of inflammation and fibrosis in pSS salivary glands and growing evidence supporting MSCs contributing to tissue homeostasis, our data suggests that dysregulation of X-inactivation maintenance, a female-specific process, contributes to the female-bias in pSS susceptibility.