A long noncoding RNA influences the choice of the X chromosome to be inactivated

Abstract

X chromosome inactivation (XCI) is the process of silencing one of the X chromosomes in cells of the female mammal which ensures dosage compensation between the sexes. Although theoretically random in somatic tissues, the choice of which X chromosome is chosen to be inactivated can be biased in mice by genetic element(s) associated with the so-called X-controlling element (<i>Xce</i>). Although the <i>Xce</i> was first described and genetically localized nearly 40 y ago, its mode of action remains elusive. In the approach presented here, we identify a single long noncoding RNA (lncRNA) within the <i>Xce</i> locus, Lppnx, which may be the driving factor in the choice of which X chromosome will be inactivated in the developing female mouse embryo. Comparing weak and strong <i>Xce</i> alleles we show that Lppnx modulates the expression of <i>Xist lncRNA</i>, one of the key factors in XCI, by controlling the occupancy of pluripotency factors at Intron1 of <i>Xist</i>. This effect is counteracted by enhanced binding of Rex1 in <i>DxPas34</i>, another key element in XCI regulating the activity of Tsix lncRNA, the main antagonist of Xist, in the strong but not in the weak <i>Xce</i> allele. These results suggest that the different susceptibility for XCI observed in weak and strong <i>Xce</i> alleles results from differential transcription factor binding of <i>Xist</i> Intron 1 and <i>DxPas34</i>, and that <i>Lppnx</i> represents a decisive factor in explaining the action of the <i>Xce</i>.