Spen links RNA-mediated endogenous retrovirus silencing and X chromosome inactivation
Ava C. Carter, Jin Xu, Meagan Y Nakamoto, Yuning Wei, Brian Zarnegar, Quanming Shi, James P. Broughton, Ryan C. Ransom, Ankit Salhotra, Surya Nagaraja, Rui Li, Diana R. Dou, Kathryn E. Yost, Seung‐Woo Cho, Anil Mistry, Michael T. Longaker, Paul A. Khavari, Robert Batey, Deborah S. Wuttke, Howard Y. Chang
Abstract
The Xist lncRNA mediates X chromosome inactivation (XCI). Here we show that Spen, an Xist-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 ERV RNA transcription. Spen binds directly to ERV RNAs that show structural similarity to the A-repeat of Xist, a region critical for Xist-mediated gene silencing. ERV RNA and Xist 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 Xist RNA to Spen and results in strictly local gene silencing in cis. These results suggest that Xist may coopt transposable element RNA-protein interactions to repurpose powerful antiviral chromatin silencing machinery for sex chromosome dosage compensation.