Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
Kathryn E Yost
Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
Seung-Woo Cho
Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
Anil Mistry
Novartis Institute for Biomedical Research, Cambridge, United States
Michael T Longaker
Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, United States; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, United States
Paul A Khavari
Department of Dermatology, Stanford University School of Medicine, Stanford, United States
Robert T Batey
Department of Biochemistry, University of Colorado, Boulder, United States
Deborah S Wuttke
Department of Biochemistry, University of Colorado, Boulder, United States
Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States; Department of Dermatology, Stanford University School of Medicine, Stanford, United States; Howard Hughes Medical Institute, Stanford University, Stanford, United States
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.
