Silent Chromatin Research Articles

DAXX Is a Crucial Factor for Proper Development of Mammalian Oocytes and Early Embryos.

The Death-domain associated protein 6 (DAXX) is an evolutionarily conserved and ubiquitously expressed multifunctional protein that is implicated in many cellular processes, including transcription, cellular proliferation, cell cycle regulation, Fas-induced apoptosis, and many other events. In the nucleus, DAXX interacts with transcription factors, epigenetic modifiers, and chromatin-remodeling proteins such as the transcription regulator ATRX—the α-thalassemia/mental retardation syndrome X-linked ATP-dependent helicase II. Accordingly, DAXX is considered one of the main players involved in chromatin silencing and one of the most important factors that maintain integrity of the genome. In this brief review, we summarize available data regarding the general and specific functions of DAXX in mammalian early development, with special emphasis on the function of DAXX as a chaperone of the histone variant H3.3. Since H3.3 plays a key role in the developmental processes, especially in the pronounced rearrangements of heterochromatin compartment during oogenesis and embryogenesis, DAXX can be considered as an important factor supporting proper development. Specifically, loss of DAXX affects the recruitment of ATRX, transcription of tandem repeats and telomere functions, which results in a decrease in the viability of early embryos.

Cohesin promotes HSV-1 lytic transcription by facilitating the binding of RNA Pol II on viral genes

BackgroundHerpes Simplex Virus type I (HSV-1) is a large double-stranded DNA virus that enters productive infection in epithelial cells and reorganizes the host nucleus. Cohesin, a major constituent of interphase and mitotic chromosomes comprised of SMC1, SMC3, and SCC1 (Mcd1/Rad21), SCC3 (SA1/SA2), have diverse functions, including sister chromatid cohesion, DNA double-stranded breaks repair, and transcriptional control. Little is known about the role of cohesin in HSV-1 lytic infection.MethodsWe measured the effect on HSV-1 transcription, genome copy number, and viral titer by depleting cohesin components SMC1 or Rad21 using RNAi, followed by immunofluorescence, qPCR, and ChIP experiments to gain insight into cohesin's function in HSV-1 transcription and replication.ResultsHere, we report that cohesion subunits SMC1 and Rad21 are recruited to the lytic HSV-1 replication compartment. The knockdown results in decreased viral transcription, protein expression, and maturation of viral replication compartments. SMC1 and Rad21 knockdown leads to the reduced overall RNA pol II occupancy level but increased RNA pol II ser5 phosphorylation binding on viral genes. Consistent with this, the knockdown increased H3K27me3 modification on these genes.ConclusionsThese results suggest that cohesin facilitates HSV-1 lytic transcription by promoting RNA Pol II transcription activity and preventing chromatin's silencing on the viral genome.

The Essential Function of SETDB1 in Homologous Chromosome Pairing and Synapsis during Meiosis

SETDB1 is a histone-lysine N-methyltransferase critical for germline development. However, its function in early meiotic prophase I remains unknown. Here, we report that Setdb1 null spermatocytes display aberrant centromere clustering during leptotene, bouquet formation during zygotene, and subsequent failure in pairing and synapsis of homologous chromosomes, as well as compromised meiotic silencing of unsynapsed chromatin, which leads to meiotic arrest before pachytene and apoptosis of spermatocytes. H3K9me3 is enriched in centromeric or pericentromeric regions and is present in many sites throughout the genome, with a subset changed in the Setdb1 mutant. These observations indicate that SETDB1-mediated H3K9me3 is essential for the bivalent formation in early meiosis. Transcriptome analysis reveals the function of SETDB1 in repressing transposons and transposon-proximal genes and in regulating meiotic and somatic lineage genes. These findings highlight a mechanism in which SETDB1-mediated H3K9me3 during early meiosis ensures the formation of homologous bivalents and survival of spermatocytes.

Meiotic self-pairing of the Psalidodon (Characiformes, Characidae) iso-B chromosome: A successful perpetuation mechanism.

B chromosomes are non-essential additional genomic elements present in several animal and plant species. In fishes, species of the genus Psalidodon (Characiformes, Characidae) harbor great karyotype diversity, and multiple populations carry different types of non-essential B chromosomes. This study analyzed how the dispensable supernumerary B chromosome of Psalidodon paranae behaves during meiosis to overcome checkpoints and express its own meiosis-specific genes. We visualized the synaptonemal complexes of P. paranae individuals with zero, one, or two B chromosomes using immunodetection with anti-medaka SYCP3 antibody and fluorescence in situ hybridization with a (CA)15 microsatellite probe. Our results showed that B chromosomes self-pair in cells containing only one B chromosome. In cells with two identical B chromosomes, these elements remain as separate synaptonemal complexes or close self-paired elements in the nucleus territory. Overall, we reveal that B chromosomes can escape meiotic silencing of unsynapsed chromatin through a self-pairing process, allowing expression of their own genes to facilitate regular meiosis resulting in fertile individuals. This behavior, also seen in other congeneric species, might be related to their maintenance throughout the evolutionary history of Psalidodon.

New Insights into X-Chromosome Reactivation during Reprogramming to Pluripotency.

Dosage compensation between the sexes results in one X chromosome being inactivated during female mammalian development. Chromosome-wide transcriptional silencing from the inactive X chromosome (Xi) in mammalian cells is erased in a process termed X-chromosome reactivation (XCR), which has emerged as a paradigm for studying the reversal of chromatin silencing. XCR is linked with germline development and induction of naive pluripotency in the epiblast, and also takes place upon reprogramming somatic cells to induced pluripotency. XCR depends on silencing of the long non-coding RNA (lncRNA) X inactive specific transcript (Xist) and is linked with the erasure of chromatin silencing. Over the past years, the advent of transcriptomics and epigenomics has provided new insights into the transcriptional and chromatin dynamics with which XCR takes place. However, multiple questions remain unanswered about how chromatin and transcription related processes enable XCR. Here, we review recent work on establishing the transcriptional and chromatin kinetics of XCR, as well as discuss a model by which transcription factors mediate XCR not only via Xist repression, but also by direct targeting of X-linked genes.

Sirtuins: New Roles for Sirtuins in Aging and Disease

Sirtuins are NAD+-dependent enzymes related to yeast silent information regulator-2, a histone deacetylase that prevents premature aging through chromatin silencing. Mammalian sirtuins, SIRT1-SIRT7, have key functions that protect against diverse aging-related pathologic states, from cancer to metabolic and neurodegenerative disease. In addition to chromatin regulation, mammalian sirtuins also govern myriad cellular processes through a growing list of enzymatic activities and substrates. This session will highlight new discoveries and directions in Sirtuin research.

Sirt6 Deacetylase: A Potential Key Regulator in the Prevention of Obesity, Diabetes and Neurodegenerative Disease.

Sirtuins, NAD + dependent proteins belonging to class III histone deacetylases, are involved in regulating numerous cellular processes including cellular stress, insulin resistance, inflammation, mitochondrial biogenesis, chromatin silencing, cell cycle regulation, transcription, and apoptosis. Of the seven mammalian sirtuins present in humans, Sirt6 is an essential nuclear sirtuin. Until recently, Sirt6 was thought to regulate chromatin silencing, but new research indicates its role in aging, diabetes, cardiovascular disease, lipid metabolism, neurodegenerative diseases, and cancer. Various murine models demonstrate that Sirt6 activation is beneficial in alleviating many disease conditions and increasing lifespan, showing that Sirt6 is a critical therapeutic target in the treatment of various disease conditions in humans. Sirt6 also regulates the pathogenesis of multiple diseases by acting on histone proteins and non-histone proteins. Endogenous and non-endogenous modulators regulate both activation and inhibition of Sirt6. Few Sirt6 specific non-endogenous modulators have been identified. Hence the identification of Sirt6 specific modulators may have potential therapeutic roles in the diseases described above. In this review, we describe the development of Sirt6, the role it plays in the human condition, the functional role and therapeutic importance in disease processes, and specific modulators and molecular mechanism of Sirt6 in the regulation of metabolic homeostasis, cardiovascular disease, aging, and neurodegenerative disease.

Protein anabolism is key to long-term survival in high-grade serous ovarian cancer

This study aimed to identify the biological processes associated with long-term survival in high-grade serous ovarian cancer (HGSOC). HGSOC cases obtained from The Cancer Genome Atlas Ovarian Cancer (TCGA-OV) database were divided into long-term survivors (LTS) and normal-term survivors (NTS) based on survival cutoffs defined by the HGSOC cohort in the SEER database. Differentially expressed genes (DEGs) were screened using the generalized linear modeling (GLM) method. Gene Ontology (GO) functional and KEGG pathway enrichment analyses were performed using DAVID Bioinformatics Resources. DEG-related protein-protein interactions (PPI) were extracted from the STRING database and hub genes were identified using CytoHubba in the Cytoscape program. In total, 157 DEGs, including 155 upregulated and 2 downregulated genes, were identified. Upregulated genes were statistically enriched in 80 GO terms and 11 KEGG pathways related to energy and substrate metabolism, such as protein absorption, digestion, and metabolism as well as signaling pathways, including chromatin silencing, regulation of ERK1 and ERK2 cascade, and regulation of MAPKKK. ALB and POMC were the common hub genes. These findings reveal that protein anabolism is crucial to long-term survival, regulated by activation of the MAPK/ERK signaling pathway and chromatin silencing. Comprehensive understanding of the molecular mechanisms via further exploration may contribute toward an effective treatment for ovarian cancer.

Gene expression profiling of chromosome 10 in PTEN-knockout (−/−) human neural and mesenchymal stem cells: A system biology study

The present study investigates the effects of PTEN deletion in human neuro and mesenchymal stem cells related to the chromosome 10 gene expression profile. The RNA sequencing (RNA-seq) performed on four neural and four mesenchymal stem cells. DEG analysis outcome revealed 122 genes for neural stem cells (57 up-regulated and 65 down-regulated genes) and 258 genes for mesenchymal stem cells (98 up-regulated and 160 down-regulated genes) that were deferentially expressed in the PTEN (-/-) group compared to the normal group. Gene ontology analysis indicated that in the NSCs upregulated DEGs were significantly enriched in transcriptional activator activity, phosphatidylinositol phosphate phosphatase activity, MAP kinase activity while the downregulated DEGs were mainly involved in glycolytic process through glucose-6-phosphate, canonical glycolysis, glucose catabolic process to pyruvate. Meanwhile, in MSCs, the upregulated DEGs were mainly enriched in positive regulation of cell migration, chromatin silencing complex, RNA polymerase core enzyme binding while the downregulated DEGs phosphofructokinase activity, focal adhesion, glycolytic process through glucose-6-phosphate. On the basis of the PPI network of the DEGs, the following top hub genes were detected: six hub genes (PTEN, MAPK8, VCL, PAX2, ITGB1 and RET) in neural stem cells and 9 hub genes (PTEN, CDK1, KIF11, VCL, HK1, KIF20B, SIRT1, ACTR1A and ITGB1) appeared in mesenchymal stem cells respectively in each of the top 10 gene lists. In conclusion, PTEN, VCL and ITGB are found to be the main hub genes in both neural and mesenchymal stem cells, which involve in cell cycle, tumor progression and metastasis.

Regulation and Roles of the Nucleolus in Embryonic Stem Cells: From Ribosome Biogenesis to Genome Organization.

The nucleolus is the largest compartment of the eukaryotic cell's nucleus. It acts as a ribosome factory, thereby sustaining the translation machinery. The nucleolus is also the subnuclear compartment with the highest transcriptional activity in the cell, where hundreds of ribosomal RNA (rRNA) genes transcribe the overwhelming majority of RNAs. The structure and composition of the nucleolus change according to the developmental state. For instance, in embryonic stem cells (ESCs), rRNA genes display a hyperactive transcriptional state and open chromatin structure compared with differentiated cells. Increasing evidence indicates that the role of the nucleolus and rRNA genes might go beyond the control of ribosome biogenesis. One such role is linked to the genome architecture, since repressive domains are often located close to the nucleolus. This review highlights recent findings describing how the nucleolus is regulated in ESCs and its role in regulating ribosome biogenesis and genome organization for the maintenance of stem cell identity.

YTHDF2/3 Are Required for Somatic Reprogramming through Different RNA Deadenylation Pathways

N6-methyladenosine (m6A), the most abundant reversible modification on eukaryote messenger RNA, is recognized by a series of readers, including the YT521-B homology domain family (YTHDF) proteins, which are coupled to perform physiological functions. Here, we report that YTHDF2 and YTHDF3, but not YTHDF1, are required for reprogramming of somatic cells into induced pluripotent stem cells (iPSCs). Mechanistically, we found that YTHDF3 recruits the PAN2-PAN3 deadenylase complex and conduces to reprogramming by promoting mRNA clearance of somatic genes, including Tead2 and Tgfb1, which parallels the activity of the YTHDF2-CCR4-NOT deadenylase complex. Ythdf2/3 deficiency represses mesenchymal-to-epithelial transition (MET) and chromatin silencing at loci containing the TEAD motif, contributing to decreased reprogramming efficiency. Moreover, RNA interference of Tgfb1 or the Hippo signaling effectors Yap1, Taz, and Tead2 rescues Ythdf2/3-defective reprogramming. Overall, YTHDF2/3 couples RNA deadenylation and regulation with the clearance of somatic genes and provides insights into iPSC reprogramming at the posttranscriptional level.

SIR2 Expression Noise Can Generate Heterogeneity in Viability but Does Not Affect Cell-to-Cell Epigenetic Silencing of Subtelomeric URA3 in Yeast.

Chromatin structure clearly modulates gene expression noise, but the reverse influence has never been investigated, namely how the cell-to-cell expression heterogeneity of chromatin modifiers may generate variable rates of epigenetic modification. Sir2 is a well-characterized histone deacetylase of the Sirtuin family. It strongly influences chromatin silencing, especially at telomeres, subtelomeres and rDNA. This ability to influence epigenetic landscapes makes it a good model to study the largely unexplored interplay between gene expression noise and other epigenetic processes leading to phenotypic diversification. Here, we addressed this question by investigating whether noise in the expression of SIR2 was associated with cell-to-cell heterogeneity in the frequency of epigenetic silencing at subtelomeres in Saccharomyces cerevisiae. Using cell sorting to isolate subpopulations with various expression levels, we found that heterogeneity in the cellular concentration of Sir2 does not lead to heterogeneity in the epigenetic silencing of subtelomeric URA3 between these subpopulations. We also noticed that SIR2 expression noise can generate cell-to-cell variability in viability, with lower levels being associated with better viability. This work shows that SIR2 expression fluctuations are not sufficient to generate cell-to-cell heterogeneity in the epigenetic silencing of URA3 at subtelomeres in Saccharomyces cerevisiae but can strongly affect cellular viability.

S-phase-independent silencing establishment in Saccharomyces cerevisiae.

The establishment of silent chromatin, a heterochromatin-like structure at HML and HMR in Saccharomyces cerevisiae, depends on progression through S phase of the cell cycle, but the molecular nature of this requirement has remained elusive despite intensive study. Using high-resolution chromatin immunoprecipitation and single-molecule RNA analysis, we found that silencing establishment proceeded via gradual repression of transcription in individual cells over several cell cycles, and that the cell-cycle-regulated step was downstream of Sir protein recruitment. In contrast to prior results, HML and HMR had identical cell-cycle requirements for silencing establishment, with no apparent contribution from a tRNA gene adjacent to HMR. We identified the cause of the S-phase requirement for silencing establishment: removal of transcription-favoring histone modifications deposited by Dot1, Sas2, and Rtt109. These results revealed that silencing establishment was absolutely dependent on the cell-cycle-regulated interplay between euchromatic and heterochromatic histone modifications.

Structure and function of Pygo in organ development dependent and independent Wnt signalling.

Pygo is a nuclear protein containing two conserved domains, NHD and PHD, which play important roles in embryonic development and carcinogenesis. Pygo was first identified as a core component of the Wnt/β-catenin signalling pathway. However, it has also been reported that the function of Pygo is not always Wnt/β-catenin signalling dependent. In this review, we summarise the functions of both domains of Pygo and show that their functions are synergetic. The PHD domain mainly combines with transcription co-factors, including histone 3 and Bcl9/9l. The NHD domain mainly recruits histone methyltransferase/acetyltransferase (HMT/HAT) to modify lysine 4 of the histone 3 tail (H3K4) and interacts with Chip/LIM-domain DNA-binding proteins (ChiLS) to form enhanceosomes to regulate transcriptional activity. Furthermore, we summarised chromatin modification differences of Pygo in Drosophila (dPygo) and vertebrates, and found that Pygo displayes a chromatin silencing function in Drosophila, while in vertebates, Pygo has a chromatin-activating function due to the two substitution of two amino acid residues. Next, we confirmed the relationship between Pygo and Bcl9/9l and found that Pygo-Bcl/9l are specifically partnered both in the nucleus and in the cytoplasm. Finally, we discuss whether transcriptional activity of Pygo is Wnt/β-catenin dependent during embryonic development. Available information indications that the transcriptional activity of Pygo in embryonic development is either Wnt/β-catenin dependent or independent in both tissue-specific and cell-specific-modes.

Direct readout of heterochromatic H3K9me3 regulates DNMT1-mediated maintenance DNA methylation

In mammals, repressive histone modifications such as trimethylation of histone H3 Lys9 (H3K9me3), frequently coexist with DNA methylation, producing a more stable and silenced chromatin state. However, it remains elusive how these epigenetic modifications crosstalk. Here, through structural and biochemical characterizations, we identified the replication foci targeting sequence (RFTS) domain of maintenance DNA methyltransferase DNMT1, a module known to bind the ubiquitylated H3 (H3Ub), as a specific reader for H3K9me3/H3Ub, with the recognition mode distinct from the typical trimethyl-lysine reader. Disruption of the interaction between RFTS and the H3K9me3Ub affects the localization of DNMT1 in stem cells and profoundly impairs the global DNA methylation and genomic stability. Together, this study reveals a previously unappreciated pathway through which H3K9me3 directly reinforces DNMT1-mediated maintenance DNA methylation.

A partially disordered region connects gene repression and activation functions of EZH2

Enhancer of Zeste Homolog 2 (EZH2) is the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), which minimally requires two other subunits, EED and SUZ12, for enzymatic activity. EZH2 has been traditionally known to mediate histone H3K27 trimethylation, a hallmark of silent chromatin. Emerging evidence indicates that EZH2 also activates gene expression in cancer cells in a context distinct from canonical PRC2. The molecular mechanism underlying the functional conversion of EZH2 from a gene repressor to an activator is unclear. Here, we show that EZH2 harbors a hidden, partially disordered transactivation domain (TAD) capable of interacting with components of active transcription machinery, mimicking archetypal acidic activators. The EZH2 TAD comprises the SRM (Stimulation-Responsive Motif) and SANT1 (SWI3, ADA2, N-CoR, and TFIIIB 1) regions that are normally involved in H3K27 methylation. The crystal structure of an EZH2-EED binary complex indicates that the EZH2 TAD mediates protein oligomerization in a noncanonical PRC2 context and is entirely sequestered. The EZH2 TAD can be unlocked by cancer-specific EZH2 phosphorylation events to undergo structural transitions that may enable subsequent transcriptional coactivator binding. The EZH2 TAD directly interacts with the transcriptional coactivator and histone acetyltransferase p300 and activates gene expression in a p300-dependent manner in cells. The corresponding TAD may also account for the gene activation function of EZH1, the paralog of EZH2. Distinct kinase signaling pathways that are known to abnormally convert EZH2 into a gene activator in cancer cells can now be understood in a common structural context of the EZH2 TAD.

The CCR4-NOT complex component NOT1 regulates RNA-directed DNA methylation and transcriptional silencing by facilitating Pol IV-dependent siRNA production.

Small interfering RNAs (siRNAs) are responsible for establishing and maintaining DNA methylation through the RNA-directed DNA methylation (RdDM) pathway in plants. Although siRNA biogenesis is well known, it is relatively unclear about how the process is regulated. By a forward genetic screen in Arabidopsis thaliana, we identified a mutant defective in NOT1 and demonstrated that NOT1 is required for transcriptional silencing at RdDM target genomic loci. We demonstrated that NOT1 is required for Pol IV-dependent siRNA accumulation and DNA methylation at a subset of RdDM target genomic loci. Furthermore, we revealed that NOT1 is a constituent of a multi-subunit CCR4-NOT deadenylase complex by immunoprecipitation combined with mass spectrometry and demonstrated that the CCR4-NOT components can function as a whole to mediate chromatin silencing. Therefore, our work establishes that the CCR4-NOT complex regulates the biogenesis of Pol IV-dependent siRNAs, and hence facilitates DNA methylation and transcriptional silencing in Arabidopsis.

The 3′ processing of antisense RNAs physically links to chromatin-based transcriptional control

Noncoding RNA plays essential roles in transcriptional control and chromatin silencing. At Arabidopsis thaliana FLC, antisense transcription quantitatively influences transcriptional output, but the mechanism by which this occurs is still unclear. Proximal polyadenylation of the antisense transcripts by FCA, an RNA-binding protein that physically interacts with RNA 3' processing factors, reduces FLC transcription. This process genetically requires FLD, a homolog of the H3K4 demethylase LSD1. However, the mechanism linking RNA processing to FLD function had not been established. Here, we show that FLD tightly associates with LUMINIDEPENDENS (LD) and SET DOMAIN GROUP 26 (SDG26) in vivo, and, together, they prevent accumulation of monomethylated H3K4 (H3K4me1) over the FLC gene body. SDG26 interacts with the RNA 3' processing factor FY (WDR33), thus linking activities for proximal polyadenylation of the antisense transcripts to FLD/LD/SDG26-associated H3K4 demethylation. We propose this demethylation antagonizes an active transcription module, thus reducing H3K36me3 accumulation and increasing H3K27me3. Consistent with this view, we show that Polycomb Repressive Complex 2 (PRC2) silencing is genetically required by FCA to repress FLC Overall, our work provides insights into RNA-mediated chromatin silencing.

EZH2 inhibitors-mediated epigenetic reactivation of FOSB inhibits triple-negative breast cancer progress

BackgroundTriple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer that lacks expression of estrogen receptor (ER) and progesterone receptor (PR) and the human epidermal growth factor receptor 2 (HER2) gene. Chemotherapy remains the standard of care for TNBC treatment, but considerable patients are very resistant to chemotherapy. Mutations or aberrant upregulation of EZH2 occur frequently, and EZH2 inhibitor (EZH2i) showed some preclinic antitumor effects in TNBC.MethodsRNA-seq data of 3 TNBC cell lines either treated with 2 μM GSK343, or stably transduced with shEHZ2, compared to untreated controls (GSE112378) were analyzed by Limma R package. The Kaplan–Meier plotter (KM plotter) database was used to assess the relevance of FOSB mRNA expression to relapse-free survival (RFS) in TNBC. Cell number counting and colony formation assays were used to detect the biological effect of FOSB on the growth of TNBC cells in vitro. The effect of FOSB on TNBC tumor growth in vivo was investigated in a mice tumor xenograft model. Luciferase reporter and chromatin immunoprecipitation (Chip) assays were used to determine the regulatory roles of C/EBPβ on FOSB expression.ResultsWe found that FOSB, a member of the activator protein-1 complex, was a direct downstream target of EZH2. FOSB was significantly decreased in TNBC samples and associated with better relapse-free survival (RFS). EZH2-mediated histone 3 trimethylated on lysine 27 (H3K27me3), a marker of silent chromatin conformation, at the FOSB promoter inhibited it expression. Depletion of FOSB in TNBC cells promoted cell proliferation in vitro and tumor growth in vitro by inactivating the p53 pathway and conferred resistant to EZH2 inhibitor (EZH2i). Mechanistically, EZH2i promotes the shift from H3K27me3 to H3K27ac at the FOSB promoter, and recruits the transcription factor C/EBPβ to activate FOSB gene transcription.ConclusionTogether, our results suggest that EZH2-mediated epigenetic inactivation of FOSB promotes TNBC expression and demonstrate that reactivation of FOSB expression by C/EBPβ underlies the anti-TNBC action of EZH2is.

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

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.