Unusual maintenance of X chromosome inactivation predisposes female lymphocytes for increased expression from the inactive X

TLDR

Females exhibit heightened immune responsiveness and a higher incidence of autoimmune disorders, yet the underlying mechanism remains unclear, with the X chromosome suspected to play a key role. We show that the inactive X in female lymphocytes is prone to partial reactivation, leading to overexpression of immunity genes, and that lupus patients display epigenetic alterations on the inactive X that weaken transcriptional silencing, linking X‑chromosome inactivation maintenance to female‑biased immunity and autoimmunity.

Abstract

Significance Females have increased immune responsiveness than males, and they are more likely to develop autoimmune disorders. The mechanism underlying these observations is unclear, and hypotheses suggest an important role for the X chromosome. Here, we discover that the inactive X is predisposed to become partially reactivated in mammalian female lymphocytes, resulting in the overexpression of immunity-related genes. We also demonstrate that lymphocytes from systemic lupus erythematosus patients have different epigenetic characteristics on the inactive X that compromises transcriptional silencing. These findings are the first to our knowledge to link the unusual maintenance of X chromosome Inactivation (the female-specific mechanism for dosage compensation) in lymphocytes to the female bias observed with enhanced immunity and autoimmunity susceptibility.