Spen links RNA-mediated endogenous retrovirus silencing and X chromosome inactivation

Abstract

The <i>Xist</i> lncRNA mediates X chromosome inactivation (XCI). Here we show that Spen, an <i>Xist</i>-binding repressor protein essential for XCI , binds to ancient retroviral RNA, performing a surveillance role to recruit chromatin silencing machinery to these parasitic loci. Spen loss activates a subset of endogenous retroviral (ERV) elements in mouse embryonic stem cells, with gain of chromatin accessibility, active histone modifications, and <i>ERV</i> RNA transcription. Spen binds directly to <i>ERV</i> RNAs that show structural similarity to the A-repeat of <i>Xist</i>, a region critical for <i>Xist</i>-mediated gene silencing. <i>ERV</i> RNA and <i>Xist</i> A-repeat bind the RRM domains of Spen in a competitive manner. Insertion of an ERV into an A-repeat deficient Xist rescues binding of <i>Xist</i> RNA to Spen and results in strictly local gene silencing in <i>cis</i>. These results suggest that <i>Xist</i> may coopt transposable element RNA-protein interactions to repurpose powerful antiviral chromatin silencing machinery for sex chromosome dosage compensation.