Dynamic mechanisms of Xist RNA localization in female lymphocytes: a new form of X‐chromosome Inactivation maintenance

Abstract

Females mount stronger immune responses and clear pathogens faster than males, yet they are more susceptible to autoimmune and inflammatory disorders. One important biological factor underlying this sex bias is the X‐chromosome, which is enriched for immunity‐related genes. Female mammals use X‐Chromosome Inactivation (XCI) to generate a transcriptionally silent inactive X‐chromosome enriched with heterochromatic modifications and the long noncoding RNA Xist, which equalizes gene expression between the sexes. We have discovered that XCI is maintained differently in female lymphocytes from mice and humans, where Xist RNA and heterochromatic modifications dynamically associate with the inactive X‐chromosome. Mature naïve B cells are missing Xist RNA and heterochromatin marks on the inactive X, and these marks return to most cells with in vitro stimulation. We found that the chromatin of the inactive X changes during early B cell commitment, at the pro‐B cell stage, initiated by the loss of Xist RNA localization. In mature lymphocytes, we found evidence of biallelic expression and increased dosage of immunity‐related X‐linked genes including TLR7 and CXCR3, in support of relaxed transcriptional silence from the inactive X. During B cell activation, Xist RNA is relocalized to the inactive X by the transcription factor YY1, in a novel two‐step process unique to B cells. YY1‐mediated relocalization of Xist RNA during B cell stimulation is necessary for enrichment of heterochromatin modifications and maintenance of X‐linked gene silencing. Furthermore, we examined lymphocytes from patients with systemic lupus erythematosus, an autoimmune disorder with a strong female bias, and observed mislocalized XIST RNA transcripts and evidence of biallelic expression of immunity‐related genes from both X‐chromosomes. We propose that the Xi in female lymphocytes is predisposed to become partially reactivated and to overexpress immunity‐related genes, providing the first mechanistic evidence for the female‐specific enhanced immune responses and increased susceptibility for autoimmunity.Support or Funding InformationR21 AI1240845K12 HD085848‐03This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.