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Spen links RNA-mediated endogenous retrovirus silencing and X chromosome inactivation
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Spen links RNA-mediated endogenous retrovirus silencing and X chromosome inactivation
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Spen links RNA-mediated endogenous retrovirus silencing and X chromosome inactivation
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Paper
Spen links RNA-mediated endogenous retrovirus silencing and X chromosome inactivation
2019
Overview
Dosage compensation between the sexes has emerged independently multiple times during evolution, often harnessing long noncoding RNAs (lncRNAs) to alter gene expression on the sex chromosomes. In eutherian mammals, X chromosome inactivation (XCI) in females proceeds via the lncRNA Xist, which coats one of the two X chromosomes and recruits repressive proteins to epigenetically silence gene expression in cis. How Xist evolved new functional RNA domains to recruit ancient, pleiotropic protein partners is of great interest. 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 inactivation leads to de- repression of a subset of endogenous retroviral (ERV) elements in 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 RRM3 domain 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 local gene silencing in cis. These results suggest that insertion of an ERV element into proto-Xist may have been a critical evolutionary event, which allowed Xist to coopt transposable element RNA-protein interactions to repurpose powerful antiviral chromatin silencing machinery for sex chromosome dosage compensation.
