Transient Homologous Chromosome Pairing Marks the Onset of X Inactivation

TLDR

Mammalian X inactivation silences one X chromosome in females, regulated in cis by Xite, Tsix, and Xist, and also requires trans regulation to ensure mutually exclusive silencing. The study demonstrates that interchromosomal pairing mediates communication between X chromosomes and proposes that Tsix and Xite regulate counting and mutually exclusive choice through X‑X pairing. The authors propose that Tsix and Xite regulate counting and mutually exclusive choice through interchromosomal X‑X pairing. They found that transient X‑X pairing at the onset of X inactivation is specific to the X‑inactivation center, that loss of Xite or Tsix disrupts pairing and counting/choice while ectopic X‑autosome pairing blocks endogenous X‑X pairing and initiation, demonstrating that Tsix and Xite act in both cis and trans.

Abstract

Mammalian X inactivation turns off one female X chromosome to enact dosage compensation between XX and XY individuals. X inactivation is known to be regulated in cis by Xite, Tsix, and Xist, but in principle the two Xs must also be regulated in trans to ensure mutually exclusive silencing. Here, we demonstrate that interchromosomal pairing mediates this communication. Pairing occurs transiently at the onset of X inactivation and is specific to the X-inactivation center. Deleting Xite and Tsix perturbs pairing and counting/choice, whereas their autosomal insertion induces de novo X-autosome pairing. Ectopic X-autosome interactions inhibit endogenous X-X pairing and block the initiation of X-chromosome inactivation. Thus, Tsix and Xite function both in cis and in trans. We propose that Tsix and Xite regulate counting and mutually exclusive choice through X-X pairing.