LINE-1 repeats are a defining feature of the <i>Xce</i>.

Abstract

During early development, female mammals inactivate one X chromosome to balance their X-linked gene dosage with males. While allelic choice is random in inbred mouse populations, choice can be significantly skewed in interstrain hybrids. The genetic basis of skewing has long been attributed to the mysterious "X chromosome controlling element(s)" (<i>Xce</i>) with different strengths among species, subspecies, and strains. When two X-chromosomes with different <i>Xce</i> strengths are inherited by offspring, the X chromosome with the stronger <i>Xce</i> will have a higher probability of remaining active. Here, we provide evidence that L1Tf repeats-a subfamily of long interspersed nuclear elements 1-plays a role in determining <i>Xce</i> strength. L1Tf elements form a condensed core within the inactive X (Xi) territory. Mouse strains with varying <i>Xce</i> strengths differ in the L1Tf copy number on the X chromosome, with the strength of the <i>Xce</i> allele being inversely related to L1Tf copy number. L1Tf expression mediates the <i>Xce</i> effect. However, in contrast to a prior report, L1Tf RNA does not coat the Xi. Rather, L1Tf promotes condensation of the Xi core. Intriguingly, L1Tfs recruit and sequester YY1 from active genes, accelerating XCI in cis. Thus, L1Tf copy number, expression, and binding of YY1 are key defining features of the <i>Xce</i>. We propose a model in which the <i>Xce</i> influences the choice of Xist alleles by promoting YY1 binding to the nucleation site for the initiation of Xist spreading.