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1
Clemson, C. M., J. A. McNeil, H. F. Willard, and J. B. Lawrence. "XIST RNA paints the inactive X chromosome at interphase: evidence for a novel RNA involved in nuclear/chromosome structure." Journal of Cell Biology 132, no. 3 (February 1, 1996): 259–75. http://dx.doi.org/10.1083/jcb.132.3.259.
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The XIST gene is implicated in X chromosome inactivation, yet the RNA contains no apparent open reading frame. An accumulation of XIST RNA is observed near its site of transcription, the inactive X chromosome (Xi). A series of molecular cytogenetic studies comparing properties of XIST RNA to other protein coding RNAs, support a critical distinction for XIST RNA; XIST does not concentrate at Xi simply because it is transcribed and processed there. Most notably, morphometric and 3-D analysis reveals that XIST RNA and Xi are coincident in 2- and 3-D space; hence, the XIST RNA essentially paints Xi. Several results indicate that the XIST RNA accumulation has two components, a minor one associated with transcription and processing, and a spliced major component, which stably associates with Xi. Upon transcriptional inhibition the major spliced component remains in the nucleus and often encircles the extra-prominent heterochromatic Barr body. The continually transcribed XIST gene and its polyadenylated RNA consistently localize to a nuclear region devoid of splicing factor/poly A RNA rich domains. XIST RNA remains with the nuclear matrix fraction after removal of chromosomal DNA. XIST RNA is released from its association with Xi during mitosis, but shows a unique highly particulate distribution. Collective results indicate that XIST RNA may be an architectural element of the interphase chromosome territory, possibly a component of nonchromatin nuclear structure that specifically associates with Xi. XIST RNA is a novel nuclear RNA which potentially provides a specific precedent for RNA involvement in nuclear structure and cis-limited gene regulation via higher-order chromatin packaging.
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Creamer, K. M., and J. B. Lawrence. "XIST RNA: a window into the broader role of RNA in nuclear chromosome architecture." Philosophical Transactions of the Royal Society B: Biological Sciences 372, no. 1733 (September 25, 2017): 20160360. http://dx.doi.org/10.1098/rstb.2016.0360.
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XIST RNA triggers the transformation of an active X chromosome into a condensed, inactive Barr body and therefore provides a unique window into transitions of higher-order chromosome architecture. Despite recent progress, how XIST RNA localizes and interacts with the X chromosome remains poorly understood. Genetic engineering of XIST into a trisomic autosome demonstrates remarkable capacity of XIST RNA to localize and comprehensively silence that autosome. Thus, XIST does not require X chromosome-specific sequences but operates on mechanisms available genome-wide. Prior results suggested XIST localization is controlled by attachment to the insoluble nuclear scaffold. Our recent work affirms that scaffold attachment factor A (SAF-A) is involved in anchoring XIST , but argues against the view that SAF-A provides a unimolecular bridge between RNA and the chromosome. Rather, we suggest that a complex meshwork of architectural proteins interact with XIST RNA. Parallel work studying the territory of actively transcribed chromosomes suggests that repeat-rich RNA ‘coats’ euchromatin and may impact chromosome architecture in a manner opposite of XIST . A model is discussed whereby RNA may not just recruit histone modifications, but more directly impact higher-order chromatin condensation via interaction with architectural proteins of the nucleus. This article is part of the themed issue ‘X-chromosome inactivation: a tribute to Mary Lyon’.
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Rodermund, Lisa, Heather Coker, Roel Oldenkamp, Guifeng Wei, Joseph Bowness, Bramman Rajkumar, Tatyana Nesterova, David Miguel Susano Pinto, Lothar Schermelleh, and Neil Brockdorff. "Time-resolved structured illumination microscopy reveals key principles of Xist RNA spreading." Science 372, no. 6547 (June 10, 2021): eabe7500. http://dx.doi.org/10.1126/science.abe7500.
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X-inactive specific transcript (Xist) RNA directs the process of X chromosome inactivation in mammals by spreading in cis along the chromosome from which it is transcribed and recruiting chromatin modifiers to silence gene transcription. To elucidate mechanisms of Xist RNA cis-confinement, we established a sequential dual-color labeling, super-resolution imaging approach to trace individual Xist RNA molecules over time, which enabled us to define fundamental parameters of spreading. We demonstrate a feedback mechanism linking Xist RNA synthesis and degradation and an unexpected physical coupling between preceding and newly synthesized Xist RNA molecules. Additionally, we find that the protein SPEN, a key factor for Xist-mediated gene silencing, has a distinct function in Xist RNA localization, stability, and coupling behaviors. Our results provide insights toward understanding the distinct dynamic properties of Xist RNA.
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Clemson, Christine Moulton, Jennifer C. Chow, Carolyn J. Brown, and Jeanne Bentley Lawrence. "Stabilization and Localization of Xist RNA are Controlled by Separate Mechanisms and are Not Sufficient for X Inactivation." Journal of Cell Biology 142, no. 1 (July 13, 1998): 13–23. http://dx.doi.org/10.1083/jcb.142.1.13.
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These studies address whether XIST RNA is properly localized to the X chromosome in somatic cells where human XIST expression is reactivated, but fails to result in X inactivation (Tinker, A.V., and C.J. Brown. 1998. Nucl. Acids Res. 26:2935–2940). Despite a nuclear RNA accumulation of normal abundance and stability, XIST RNA does not localize in reactivants or in naturally inactive human X chromosomes in mouse/ human hybrid cells. The XIST transcripts are fully stabilized despite their inability to localize, and hence XIST RNA localization can be uncoupled from stabilization, indicating that these are separate steps controlled by distinct mechanisms. Mouse Xist RNA tightly localized to an active X chromosome, demonstrating for the first time that the active X chromosome in somatic cells is competent to associate with Xist RNA. These results imply that species-specific factors, present even in mature, somatic cells that do not normally express Xist, are necessary for localization. When Xist RNA is properly localized to an active mouse X chromosome, X inactivation does not result. Therefore, there is not a strict correlation between Xist localization and chromatin inactivation. Moreover, expression, stabilization, and localization of Xist RNA are not sufficient for X inactivation. We hypothesize that chromosomal association of XIST RNA may initiate subsequent developmental events required to enact transcriptional silencing.
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Coker, Heather, Guifeng Wei, Benoit Moindrot, Shabaz Mohammed, Tatyana Nesterova, and Neil Brockdorff. "The role of the Xist 5’ m6A region and RBM15 in X chromosome inactivation." Wellcome Open Research 5 (February 17, 2020): 31. http://dx.doi.org/10.12688/wellcomeopenres.15711.1.
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Background: X chromosome inactivation in mammals is regulated by the non-coding (nc) RNA, Xist, which represses the chromosome from which it is transcribed. High levels of the N6-methyladenosine (m6A) RNA modification occur within Xist exon I, close to the 5’ end of the transcript, and also further 3’, in Xist exon VII. The m6A modification is catalysed by the METTL3/14 complex that is directed to specific targets, including Xist, by the RNA binding protein RBM15/15B. m6A modification of Xist RNA has been reported to be important for Xist–mediated gene silencing. Methods: We use CRISPR/Cas9 mediated mutagenesis to delete sequences around the 5’ m6A region in interspecific XX mouse embryonic stem cells (mESCs). Following induction of Xist RNA expression, we assay chromosome silencing using allelic RNA-seq and Xist m6A distribution using m6A-seq. Additionally, we use Xist RNA FISH to analyse the effect of deleting the 5’ m6A region on the function of the endogenous Xist promoter. We purify epitope tagged RBM15 from mESCs, and then apply MS/MS analysis to define the RBM15 interactome. Results: We show that a deletion encompassing the entire Xist 5’ m6A region results in a modest reduction in Xist-mediated silencing, and that the 5’ m6A region overlaps essential DNA elements required for activation of the endogenous Xist promoter. Deletion of the Xist A-repeat, to which RBM15 binds, entirely abolishes deposition of m6A in the Xist 5’ m6A region without affecting the modification in exon VII. We show that in mESCs, RBM15 interacts with the m6A complex, the SETD1B histone modifying complex, and several proteins linked to RNA metabolism. Conclusions: Our findings support that RBM15 binding to the Xist A-repeat recruits the m6A complex to the 5’ Xist m6A region and that this region plays a role in Xist-mediated chromosome silencing.
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Jonkers, Iris, Kim Monkhorst, Eveline Rentmeester, J. Anton Grootegoed, Frank Grosveld, and Joost Gribnau. "Xist RNA Is Confined to the Nuclear Territory of the Silenced X Chromosome throughout the Cell Cycle." Molecular and Cellular Biology 28, no. 18 (July 14, 2008): 5583–94. http://dx.doi.org/10.1128/mcb.02269-07.
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ABSTRACT In mammalian female cells, one X chromosome is inactivated to prevent a dose difference in the expression of X-encoded proteins between males and females. Xist RNA, required for X chromosome inactivation, is transcribed from the future inactivated X chromosome (Xi), where it spreads in cis, to initiate silencing. We have analyzed Xist RNA transcription and localization throughout the cell cycle. It was found that Xist transcription is constant and that the mature RNA remains attached to the Xi throughout mitosis. Diploid and tetraploid cell lines with an MS2-tagged Xist gene were used to investigate spreading of Xist. Most XXXXMS2 tetraploid mouse embryonic stem (ES) cells inactivate the XMS2 chromosome and one other X chromosome. Analysis of cells with two Xi's indicates that Xist RNA is retained by the Xi of its origin and does not spread in trans. Also, in XXMS2 diploid mouse ES cells with an autosomal Xist transgene, there is no trans exchange of Xist RNA from the Xi to the autosome. We propose that Xist RNA does not dissociate from the Xi of its origin, which precludes a model of diffusion-mediated trans spreading of Xist RNA.
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Hall, Lisa L., Meg Byron, Gayle Pageau, and Jeanne B. Lawrence. "AURKB-mediated effects on chromatin regulate binding versus release of XIST RNA to the inactive chromosome." Journal of Cell Biology 186, no. 4 (August 24, 2009): 491–507. http://dx.doi.org/10.1083/jcb.200811143.
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How XIST RNA strictly localizes across the inactive X chromosome is unknown; however, prophase release of human XIST RNA provides a clue. Tests of inhibitors that mimic mitotic chromatin modifications implicated an indirect role of PP1 (protein phosphatase 1), potentially via its interphase repression of Aurora B kinase (AURKB), which phosphorylates H3 and chromosomal proteins at prophase. RNA interference to AURKB causes mitotic retention of XIST RNA, unlike other mitotic or broad kinase inhibitors. Thus, AURKB plays an unexpected role in regulating RNA binding to heterochromatin, independent of mechanics of mitosis. H3 phosphorylation (H3ph) was shown to precede XIST RNA release, whereas results exclude H1ph involvement. Of numerous Xi chromatin (chromosomal protein) hallmarks, ubiquitination closely follows XIST RNA retention or release. Surprisingly, H3S10ph staining (but not H3S28ph) is excluded from Xi and is potentially linked to ubiquitination. Results suggest a model of multiple distinct anchor points for XIST RNA. This study advances understanding of RNA chromosome binding and the roles of AURKB and demonstrates a novel approach to manipulate and study XIST RNA.
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Shestakova, E. A., and T. A. Bogush. "BRCA1 participates in the expression of noncoding XIST RNA." Russian Journal of Biotherapy 18, no. 1 (April 19, 2019): 67–74. http://dx.doi.org/10.17650/1726-9784-2019-18-1-67-74.
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Introduction . Noncoding RNA of XIST gene (X inactivation-specific transcript) initiates inactivation of one of X chromosomes in cells of female organism. Further stages of this process include chromatin epigenetic modifications leading to the inhibition of the most genes on X chromosome. Recently the data were obtained that tumor suppressor BRCA1 is associated with inactive X chromosome (Xi) participating in XIST RNA localization on Xi and influencing XIST RNA expression.Objective: to reveal the role of BRCA1 in XIST RNA expression.Materials and methods . The objects of the study were mutant breast cancer cell lines (BRCA1–/–): HCC1395, HCC1937, SUM149PT, and, as controls – cell lines containing wild type of BRCA1 gene (BRCA1+/+): IMR90 и 293T. Method of reverse transcription coupled with polymerase chain reaction (RT-PCR) was used for the analysis of XIST RNA expression.Results . In the clone of doxycycline-inducible HCC1937 breast cancer cell line XIST RNA expression was observed upon BRCA1 induction. In HCC1395, HCC1937 and SUM149PT breast cancer cell lines containing mutant BRCA1 gene (BRCA1–/–) and nonfunctional BRCA1 protein the absence of XIST RNA expression was observed using RT-PCR. This observation indicates the indispensable role of functional BRCA1 protein in XIST RNA expression.Conclusion . Altogether, the data obtained in this study confirm the role of BRCA1 in the expression of noncoding inhibiting XIST RNA and suggest the involvement of BRCA1 in the inhibition of gene expression on Xi.
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Coker, Heather, Benoit Moindrot, Greta Pintacuda, and Neil Brockdorff. "Illuminating Xist." Biochemist 37, no. 2 (April 1, 2015): 24–27. http://dx.doi.org/10.1042/bio03702024.
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The Central Dogma proposed that RNA, encoded by DNA in the genome, acts as the template used by cells for protein production. The simplicity of RNA as a discrete mediator of information has subsequently been challenged by the discovery of non-protein-coding RNAs. Understanding of this intricate new field has been fuelled by the development of new research techniques. In this article, we consider how recent advances in microscopy have added to our current understanding of the non-coding RNA Xist (X-inactive specific transcript).
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Jiang, Di. "Visualizing Xist RNA dynamics." Science 372, no. 6547 (June 10, 2021): 1162.11–1164. http://dx.doi.org/10.1126/science.372.6547.1162-k.
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Sunwoo, Hongjae, David Colognori, John E. Froberg, Yesu Jeon, and Jeannie T. Lee. "Repeat E anchors Xist RNA to the inactive X chromosomal compartment through CDKN1A-interacting protein (CIZ1)." Proceedings of the National Academy of Sciences 114, no. 40 (September 18, 2017): 10654–59. http://dx.doi.org/10.1073/pnas.1711206114.
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X chromosome inactivation is an epigenetic dosage compensation mechanism in female mammals driven by the long noncoding RNA, Xist. Although recent genomic and proteomic approaches have provided a more global view of Xist’s function, how Xist RNA localizes to the inactive X chromosome (Xi) and spreads in cis remains unclear. Here, we report that the CDKN1-interacting zinc finger protein CIZ1 is critical for localization of Xist RNA to the Xi chromosome territory. Stochastic optical reconstruction microscopy (STORM) shows a tight association of CIZ1 with Xist RNA at the single-molecule level. CIZ1 interacts with a specific region within Xist exon 7–namely, the highly repetitive Repeat E motif. Using genetic analysis, we show that loss of CIZ1 or deletion of Repeat E in female cells phenocopies one another in causing Xist RNA to delocalize from the Xi and disperse into the nucleoplasm. Interestingly, this interaction is exquisitely sensitive to CIZ1 levels, as overexpression of CIZ1 likewise results in Xist delocalization. As a consequence, this delocalization is accompanied by a decrease in H3K27me3 on the Xi. Our data reveal that CIZ1 plays a major role in ensuring stable association of Xist RNA within the Xi territory.
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Smola, Matthew J., Thomas W. Christy, Kaoru Inoue, Cindo O. Nicholson, Matthew Friedersdorf, Jack D. Keene, David M. Lee, J. Mauro Calabrese, and Kevin M. Weeks. "SHAPE reveals transcript-wide interactions, complex structural domains, and protein interactions across the Xist lncRNA in living cells." Proceedings of the National Academy of Sciences 113, no. 37 (August 30, 2016): 10322–27. http://dx.doi.org/10.1073/pnas.1600008113.
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The 18-kb Xist long noncoding RNA (lncRNA) is essential for X-chromosome inactivation during female eutherian mammalian development. Global structural architecture, cell-induced conformational changes, and protein–RNA interactions within Xist are poorly understood. We used selective 2′-hydroxyl acylation analyzed by primer extension and mutational profiling (SHAPE-MaP) to examine these features of Xist at single-nucleotide resolution both in living cells and ex vivo. The Xist RNA forms complex well-defined secondary structure domains and the cellular environment strongly modulates the RNA structure, via motifs spanning one-half of all Xist nucleotides. The Xist RNA structure modulates protein interactions in cells via multiple mechanisms. For example, repeat-containing elements adopt accessible and dynamic structures that function as landing pads for protein cofactors. Structured RNA motifs create interaction domains for specific proteins and also sequester other motifs, such that only a subset of potential binding sites forms stable interactions. This work creates a broad quantitative framework for understanding structure–function interrelationships for Xist and other lncRNAs in cells.
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Wang, Jianle, Camille M. Syrett, Marianne C. Kramer, Arindam Basu, Michael L. Atchison, and Montserrat C. Anguera. "Unusual maintenance of X chromosome inactivation predisposes female lymphocytes for increased expression from the inactive X." Proceedings of the National Academy of Sciences 113, no. 14 (March 21, 2016): E2029—E2038. http://dx.doi.org/10.1073/pnas.1520113113.
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Females have a greater immunological advantage than men, yet they are more prone to autoimmune disorders. The basis for this sex bias lies in the X chromosome, which contains many immunity-related genes. Female mammals use X chromosome inactivation (XCI) to generate a transcriptionally silent inactive X chromosome (Xi) enriched with heterochromatic modifications and XIST/Xist RNA, which equalizes gene expression between the sexes. Here, we examine the maintenance of XCI in lymphocytes from females in mice and humans. Strikingly, we find that mature naïve T and B cells have dispersed patterns of XIST/Xist RNA, and they lack the typical heterochromatic modifications of the Xi. In vitro activation of lymphocytes triggers the return of XIST/Xist RNA transcripts and some chromatin marks (H3K27me3, ubiquitin-H2A) to the Xi. Single-cell RNA FISH analysis of female T cells revealed that the X-linked immunity genes CD40LG and CXCR3 are biallelically expressed in some cells. Using knockout and knockdown approaches, we find that Xist RNA-binding proteins, YY1 and hnRNPU, are critical for recruitment of XIST/Xist RNA back to the Xi. Furthermore, we examined B cells from patients with systemic lupus erythematosus, an autoimmune disorder with a strong female bias, and observed different XIST RNA localization patterns, evidence of biallelic expression of immunity-related genes, and increased transcription of these genes. We propose that the Xi in female lymphocytes is predisposed to become partially reactivated and to overexpress immunity-related genes, providing the first mechanistic evidence to our knowledge for the enhanced immunity of females and their increased susceptibility for autoimmunity.
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Ng, Karen, Nathalie Daigle, Aurélien Bancaud, Tatsuya Ohhata, Peter Humphreys, Rachael Walker, Jan Ellenberg, and Anton Wutz. "A system for imaging the regulatory noncoding Xist RNA in living mouse embryonic stem cells." Molecular Biology of the Cell 22, no. 14 (July 15, 2011): 2634–45. http://dx.doi.org/10.1091/mbc.e11-02-0146.
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In mammals, silencing of one of the two X chromosomes in female cells compensates for the different number of X chromosomes between the sexes. The noncoding Xist RNA initiates X chromosome inactivation. Xist spreads from its transcription site over the X chromosome territory and triggers the formation of a repressive chromatin domain. To understand localization of Xist over one X chromosome we aimed to develop a system for investigating Xist in living cells. Here we report successful visualization of transgenically expressed MS2‑tagged Xist in mouse embryonic stem cells. Imaging of Xist during an entire cell cycle shows that Xist spreads from a single point to a steady state when the chromosome is covered with a constant amount of Xist. Photobleaching experiments of the established Xist cluster indicate that chromosome‑bound Xist is dynamic and turns over on the fully Xist covered chromosome. It appears that in interphase the loss of bound Xist and newly produced Xist are in equilibrium. We also show that the turnover of bound Xist requires transcription, and Xist binding becomes stable when transcription is inhibited. Our data reveal a strategy for visualizing Xist and indicate that spreading over the chromosome might involve dynamic binding and displacement.
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Lee, David M., Jackson B. Trotman, Rachel E. Cherney, Kaoru Inoue, Megan D. Schertzer, Steven R. Bischoff, Dale O. Cowley, and J. Mauro Calabrese. "RETRACTED: A 5′ fragment of Xist can sequester RNA produced from adjacent genes on chromatin." Nucleic Acids Research 47, no. 13 (May 22, 2019): 7049–62. http://dx.doi.org/10.1093/nar/gkz432.
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Abstract Xist requires Repeat-A, a protein-binding module in its first two kilobases (2kb), to repress transcription. We report that when expressed as a standalone transcript in mouse embryonic stem cells (ESCs), the first 2kb of Xist (Xist-2kb) does not induce transcriptional silencing. Instead, Xist-2kb sequesters RNA produced from adjacent genes on chromatin. Sequestration does not spread beyond adjacent genes, requires the same sequence elements in Repeat-A that full-length Xist requires to repress transcription and can be induced by lncRNAs with similar sequence composition to Xist-2kb. We did not detect sequestration by full-length Xist, but we did detect it by mutant forms of Xist with attenuated transcriptional silencing capability. Xist-2kb associated with SPEN, a Repeat-A binding protein required for Xist-induced transcriptional silencing, but SPEN was not necessary for sequestration. Thus, when expressed in mouse ESCs, a 5′ fragment of Xist that contains Repeat-A sequesters RNA from adjacent genes on chromatin and associates with the silencing factor SPEN, but it does not induce transcriptional silencing. Instead, Xist-induced transcriptional silencing requires synergy between Repeat-A and additional sequence elements in Xist. We propose that sequestration is mechanistically related to the Repeat-A dependent stabilization and tethering of Xist near actively transcribed regions of chromatin.
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Brockdorff, Neil. "Localized accumulation of Xist RNA in X chromosome inactivation." Open Biology 9, no. 12 (December 2019): 190213. http://dx.doi.org/10.1098/rsob.190213.
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The non-coding RNA Xist regulates the process of X chromosome inactivation, in which one of the two X chromosomes present in cells of early female mammalian embryos is selectively and coordinately shut down. Remarkably Xist RNA functions in cis , affecting only the chromosome from which it is transcribed. This feature is attributable to the unique propensity of Xist RNA to accumulate over the territory of the chromosome on which it is synthesized, contrasting with the majority of RNAs that are rapidly exported out of the cell nucleus. In this review I provide an overview of the progress that has been made towards understanding localized accumulation of Xist RNA, drawing attention to evidence that some other non-coding RNAs probably function in a highly analogous manner. I describe a simple model for localized accumulation of Xist RNA and discuss key unresolved questions that need to be addressed in future studies.
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Gayen, Srimonta, Emily Maclary, Michael Hinten, and Sundeep Kalantry. "Sex-specific silencing of X-linked genes by Xist RNA." Proceedings of the National Academy of Sciences 113, no. 3 (January 6, 2016): E309—E318. http://dx.doi.org/10.1073/pnas.1515971113.
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X-inactive specific transcript (Xist) long noncoding RNA (lncRNA) is thought to catalyze silencing of X-linked genes in cis during X-chromosome inactivation, which equalizes X-linked gene dosage between male and female mammals. To test the impact of Xist RNA on X-linked gene silencing, we ectopically induced endogenous Xist by ablating the antisense repressor Tsix in mice. We find that ectopic Xist RNA induction and subsequent X-linked gene silencing is sex specific in embryos and in differentiating embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs). A higher frequency of XΔTsixY male cells displayed ectopic Xist RNA coating compared with XΔTsixX female cells. This increase reflected the inability of XΔTsixY cells to efficiently silence X-linked genes compared with XΔTsixX cells, despite equivalent Xist RNA induction and coating. Silencing of genes on both Xs resulted in significantly reduced proliferation and increased cell death in XΔTsixX female cells relative to XΔTsixY male cells. Thus, whereas Xist RNA can inactivate the X chromosome in females it may not do so in males. We further found comparable silencing in differentiating XΔTsixY and 39,XΔTsix (XΔTsixO) ESCs, excluding the Y chromosome and instead implicating the X-chromosome dose as the source of the sex-specific differences. Because XΔTsixX female embryonic epiblast cells and EpiSCs harbor an inactivated X chromosome prior to ectopic inactivation of the active XΔTsix X chromosome, we propose that the increased expression of one or more X-inactivation escapees activates Xist and, separately, helps trigger X-linked gene silencing.
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Brockdorff, Neil. "Local Tandem Repeat Expansion in Xist RNA as a Model for the Functionalisation of ncRNA." Non-Coding RNA 4, no. 4 (October 19, 2018): 28. http://dx.doi.org/10.3390/ncrna4040028.
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Xist, the master regulator of the X chromosome inactivation in mammals, is a 17 kb lncRNA that acts in cis to silence the majority of genes along the chromosome from which it is transcribed. The two key processes required for Xist RNA function, localisation in cis and recruitment of silencing factors, are genetically separable, at least in part. Recent studies have identified Xist RNA sequences and associated RNA-binding proteins (RBPs) that are important for these processes. Notably, several of the key Xist RNA elements correspond to local tandem repeats. In this review, I use examples to illustrate different modes whereby tandem repeat amplification has been exploited to allow orthodox RBPs to confer new functions for Xist-mediated chromosome inactivation. I further discuss the potential generality of tandem repeat expansion in the evolution of functional long non-coding RNAs (lncRNAs).
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Wang, Haoyou, Qiming Shen, Xin Zhang, Chunlu Yang, Su Cui, Yanbin Sun, Liming Wang, Xiaoxi Fan, and Shun Xu. "The Long Non-Coding RNA XIST Controls Non-Small Cell Lung Cancer Proliferation and Invasion by Modulating miR-186-5p." Cellular Physiology and Biochemistry 41, no. 6 (2017): 2221–29. http://dx.doi.org/10.1159/000475637.
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Background/Aims: Long non-coding RNAs (lncRNAs) are key players in the development and progression of human cancers. The lncRNA XIST (X-inactive specific transcript) has been shown to be upregulated in human non-small cell lung cancer (NSCLC); however, its role and molecular mechanisms in NSCLC cell progression remain unclear. Methods: qRT-PCR was conducted to assess the expression of XIST and miR-186. Cell proliferation was detected using MTT assay. Cell invasion and migration were evaluated using transwell assay. Cell cycle distribution and apoptosis rates were analyzed by flow cytometry. Luciferase reporter assay was used to identify the direct regulation of XIST and miR-186. A RNA immunoprecipitation was used to analyze whether XIST was associated with the RNA-induced silencing complex (RISC). Results: We confirmed that XIST was upregulated in NSCLC cell lines and tissues. Functionally, XIST knockdown inhibited cancer cell proliferation and invasion, and induced apoptosis in vitro, and suppressed subcutaneous tumor growth in vivo. Mechanistic investigations revealed a reciprocal repressive interaction between XIST and miR-186-5p. Furthermore, we showed that miR-186-5p has a binding site for XIST. Our data also indicated that XIST and miR-186-5p are likely in the same RNA induced silencing complex. Conclusion: Together, our data revealed that XIST knockdown confers suppressive function in NSCLC and XIST may be a novel therapeutic marker in this disease.
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Liu, Xingxiang, Lin Cui, and Dong Hua. "Long Noncoding RNA XIST Regulates miR-137‐EZH2 Axis to Promote Tumor Metastasis in Colorectal Cancer." Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics 27, no. 1 (December 27, 2018): 99–106. http://dx.doi.org/10.3727/096504018x15195193936573.
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We aimed to investigate the significant role of long noncoding RNA X inactive specific transcript (XIST) in regulating tumor metastasis in colorectal cancer (CRC), as well as its possible mechanism. Expression of lncRNA XIST in CRC tissues and CRC cells was detected. CRC cells were transfected with pc-XIST, blank control si-XIST, or si-control, and then the effects of lncRNA XIST on CRC cell migration and invasion were investigated, along with the interaction between lncRNA XIST and miR-137. lncRNA XIST was upregulated in CRC tissues. Compared with HT29 cells that had low metastatic potential, XIST was markedly more highly expressed in LoVo cells that had a higher metastatic potential. Overexpression of XIST promoted the migratory and invasive potential of HT29 cells, while knockdown of XIST inhibited the migratory and invasive potential of LoVo cells. Moreover, epithelial‐mesenchymal transition (EMT) markers, including E-cadherin, N-cadherin, and vimentin, exhibited corresponding expression changes. In addition, miR-137 was inhibited by XIST, and inhibition of miR-137 could reverse the effects of knockdown of XIST on the migratory and invasive potential of LoVo cells. Furthermore, enhancer of zeste homolog 2 (EZH2) was confirmed as a target of miR-137. Our data reveal that lncRNA XIST may promote tumor metastasis in CRC possibly through regulating the miR-137‐EZH2 axis. lncRNA XIST may serve as a prognostic indicator for CRC progression.
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Buzin, C. H., J. R. Mann, and J. Singer-Sam. "Quantitative RT-PCR assays show Xist RNA levels are low in mouse female adult tissue, embryos and embryoid bodies." Development 120, no. 12 (December 1, 1994): 3529–36. http://dx.doi.org/10.1242/dev.120.12.3529.
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We have investigated expression of the Xist gene in mouse female adult kidney, embryos and embryonic stem (ES) cells undergoing in vitro differentiation as embryoid bodies. Using the quantitative RT-PCR single nucleotide primer extension (SNuPE) assay, we found that the amount of Xist RNA in adult kidney of three mouse strains was less than approximately 2000 transcripts per cell, with only modest differences between strains carrying different Xce alleles. Female embryos 7.5 days post coitum had the same number of Xist transcripts per cell as isogenic adult tissue. Using quantitative oligonucleotide hybridization assays after RT-PCR, we investigated Xist expression in ES lines heterozygous at the Pgk-1 and Xist loci. We found that, while in most (XX) ES lines Xist RNA levels increased during embryoid body formation, the levels seen were less than 10% those found in adult female kidney. In addition, we found that the allelic ratio of Xist transcripts from reciprocal (XX) ES cell lines differentiating in vitro was identical to that of isogenic 10.5 to 11.5 day female embryos. These latter results suggest that there is no pattern of preferential paternal imprinting during days 1 to 9 of in vitro differentiation of ES cells. However, the influence of the Xce locus on the randomness of X-inactivation in embryos seems to operate also in ES cell lines. Our overall conclusion is that the low levels of Xist RNA in female kidney, embryos and differentiating (XX) ES cells are compatible only with models that do not require Xist RNA to cover the entire inactive X chromosome.
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Trotman, Jackson B., David M. Lee, Rachel E. Cherney, Susan O. Kim, Kaoru Inoue, Megan D. Schertzer, Steven R. Bischoff, Dale O. Cowley, and J. Mauro Calabrese. "Elements at the 5′ end of Xist harbor SPEN-independent transcriptional antiterminator activity." Nucleic Acids Research 48, no. 18 (September 28, 2020): 10500–10517. http://dx.doi.org/10.1093/nar/gkaa789.
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Abstract The Xist lncRNA requires Repeat A, a conserved RNA element located in its 5′ end, to induce gene silencing during X-chromosome inactivation. Intriguingly, Repeat A is also required for production of Xist. While silencing by Repeat A requires the protein SPEN, how Repeat A promotes Xist production remains unclear. We report that in mouse embryonic stem cells, expression of a transgene comprising the first two kilobases of Xist (Xist-2kb) causes transcriptional readthrough of downstream polyadenylation sequences. Readthrough required Repeat A and the ∼750 nucleotides downstream, did not require SPEN, and was attenuated by splicing. Despite associating with SPEN and chromatin, Xist-2kb did not robustly silence transcription, whereas a 5.5-kb Xist transgene robustly silenced transcription and read through its polyadenylation sequence. Longer, spliced Xist transgenes also induced robust silencing yet terminated efficiently. Thus, in contexts examined here, Xist requires sequence elements beyond its first two kilobases to robustly silence transcription, and the 5′ end of Xist harbors SPEN-independent transcriptional antiterminator activity that can repress proximal cleavage and polyadenylation. In endogenous contexts, this antiterminator activity may help produce full-length Xist RNA while rendering the Xist locus resistant to silencing by the same repressive complexes that the lncRNA recruits to other genes.
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Sunwoo, Hongjae, John Y. Wu, and Jeannie T. Lee. "The Xist RNA-PRC2 complex at 20-nm resolution reveals a low Xist stoichiometry and suggests a hit-and-run mechanism in mouse cells." Proceedings of the National Academy of Sciences 112, no. 31 (July 20, 2015): E4216—E4225. http://dx.doi.org/10.1073/pnas.1503690112.
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X-chromosome inactivation (XCI) is initiated by the long noncoding RNA Xist, which coats the inactive X (Xi) and targets Polycomb repressive complex 2 (PRC2) in cis. Epigenomic analyses have provided significant insight into Xist binding patterns and chromatin organization of the Xi. However, such epigenomic analyses are limited by averaging of population-wide dynamics and do not inform behavior of single cells. Here we view Xist RNA and the Xi at 20-nm resolution using STochastic Optical Reconstruction Microscopy (STORM) in mouse cells. We observe dynamics at the single-cell level not predicted by epigenomic analysis. Only ∼50 hubs of Xist RNA occur on the Xi in the maintenance phase, corresponding to 50–100 Xist molecules per Xi and contrasting with the chromosome-wide “coat” observed by deep sequencing and conventional microscopy. Likewise, only ∼50 hubs PRC2 are observed. PRC2 and Xist foci are not randomly distributed but showed statistically significant spatial association. Knock-off experiments enable visualization of the dynamics of dissociation and relocalization onto the Xi and support a functional tethering of Xist and PRC2. Our analysis reveals that Xist-PRC2 complexes are less numerous than expected and suggests methylation of nucleosomes in a hit-and-run model.
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Lv, Gong-Yi, Jun Miao, and Xiao-Lin Zhang. "Long Noncoding RNA XIST Promotes Osteosarcoma Progression by Targeting Ras-Related Protein RAP2B via miR-320b." Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics 26, no. 6 (July 5, 2018): 837–46. http://dx.doi.org/10.3727/096504017x14920318811721.
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Abnormal expression of long noncoding RNAs (lncRNAs) often contributes to the unrestricted growth and invasion of cancer cells. lncRNA X-inactive specific transcript (XIST) expression is upregulated in several cancers; however, its underlying mechanism in osteosarcoma (OS) has not been elucidated. In the present study, we found that XIST expression was significantly increased in OS tissues and cell lines by LncRNA Profiler and qRT-PCR. The effects of XIST and miR-320b on OS cell proliferation and invasion were studied by MTT and Transwell invasion assays. The competing relationship between XIST and miR-320b was confirmed by luciferase reporter assay. Our results showed that XIST knockdown strikingly inhibited cell proliferation and invasion. Furthermore, XIST could directly bind to miR-320b and repress miR-320b expression. Moreover, XIST overexpression significantly relieved the inhibition on OS cell proliferation and invasion mediated by miR-320b overexpression, which involved the derepression of Ras-related protein RAP2B. We propose that XIST is responsible for OS cell proliferation and invasion and that XIST exerts its function through the miR-320b/RAP2B axis. Our findings suggest that lncRNA XIST may be a candidate prognostic biomarker and a target for new therapies in OS patients.
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Mo, Yichao, Yaoyong Lu, Peng Wang, Simin Huang, Longguang He, Dasheng Li, Fuliang Li, et al. "Long non-coding RNA XIST promotes cell growth by regulating miR-139-5p/PDK1/AKT axis in hepatocellular carcinoma." Tumor Biology 39, no. 2 (February 2017): 101042831769099. http://dx.doi.org/10.1177/1010428317690999.
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Abnormal expression of long non-coding RNA often contributes to unrestricted growth of cancer cells. Long non-coding RNA XIST expression is upregulated in several cancers; however, its modulatory mechanisms have not been reported in hepatocellular carcinoma. In this study, we found that XIST expression was significantly increased in hepatocellular carcinoma tissues and cell lines. XIST promoted cell cycle progression from the G1 phase to the S phase and protected cells from apoptosis, which contributed to hepatocellular carcinoma cell growth. In addition, we revealed that there was reciprocal repression between XIST and miR-139-5p. PDK1 was identified as a direct target of miR-139-5p. We proposed that XIST was responsible for hepatocellular carcinoma cell proliferation, and XIST exerted its function through the miR-139-5p/PDK1 axis.
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Shestakova, E. A., and T. A. Bogush. "BRCa1 participates in XIST RNa localization on inactive x chromosome." Russian Journal of Biotherapy 18, no. 2 (June 15, 2019): 21–26. http://dx.doi.org/10.17650/1726-9784-2019-18-2-21-26.
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Introduction . Inactive X chromosome (Xi) is associated with noncoding XIST RNA, series of proteins and contains multiple epigenetic modifications that altogether determine a silence of the most of X-linked genes. Recently the data were obtained that tumor suppressor BRCA1 is also associated with Xi. The purpose of this study was to reveal the colocalization of BRCA1 and XIST RNA and precise spatial organization on Xi with the high resolution of confocal microscopy.Materials and methods . The object of the study is IMR90hTERT diploid immortalized fibroblast cell line. For BRCA1 and XIST RNA colocalization analysis on Xi the method of fluorescent hybridization in situ associated with immunofluorescent cell staining (immunoFISH) and confocal microscopy were used. For BRCA1 and heterochromatin protein-1 colocalization study the method of double immunofluorescent staining and common fluorescent microscopy were applied. Results . The study using confocal fluorescent microscopy with higher resolution has demonstrated at first the colocalization of BRCA1 with XIST RNA region of Xi revealed with XIST RNA probes and with replicating Xi and autosomes revealed with BrdU in late S-phase of cell cycle. Altogether, the data obtained suggest the involvement of BRCA1 in the inhibition of gene expression on Xi due to the regulation of XIST RNA association with Xi. Moreover, according to the results of confocal microscopy, BRCA1 also colocalizes with replicating Xi and autosomes revealed with BrdU in late S-phase of cell cycle. This indicates a possible involvement of this protein in the replication of pericentromeric repeats in cellular chromosomes. Colocalization of BRCA1 with heterochromatin protein-1α presented in pericentromeric regions of all chromosomes supports this suggestion.Conclusions . Altogether, the data obtained in this study suggest the involvement of BRCA1 in the inhibition of gene expression on Xi due to the association with noncoding inhibiting XIST RNA and in replication of heterochromatin regions.
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Minks, Jakub, and Carolyn J. Brown. "Getting to the center of X-chromosome inactivation: the role of transgenesThis paper is one of a selection of papers published in this Special Issue, entitled 30th Annual International Asilomar Chromatin and Chromosomes Conference, and has undergone the Journal’s usual peer review process." Biochemistry and Cell Biology 87, no. 5 (October 2009): 759–66. http://dx.doi.org/10.1139/o09-040.
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X-chromosome inactivation is a fascinating epigenetic phenomenon that is initiated by expression of a noncoding (nc)RNA, XIST, and results in transcriptional silencing of 1 female X. The process requires a series of events that begins even before XIST expression, and culminates in an active and a silent X within the same nucleus. We will focus on the role that transgenic systems have served in the current understanding of the process of X-chromosome inactivation, both in the initial delineation of an active and inactive X, and in the function of the XIST RNA. X inactivation is strictly cis-limited; recent studies have revealed elements within the X-inactivation center, the region required for inactivation, that are critical for the initial regulation of Xist expression and chromosome pairing. It has been revealed that the X-inactivation center contains a remarkable compendium of cis-regulatory elements, ncRNAs, and trans-acting pairing regions. We review the functional componentry of the X-inactivation center and discuss experiments that helped to dissect the XIST/Xist RNA and its involvement in the establishment of facultative heterochromatin.
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Csankovszki, Györgyi, András Nagy, and Rudolf Jaenisch. "Synergism of Xist Rna, DNA Methylation, and Histone Hypoacetylation in Maintaining X Chromosome Inactivation." Journal of Cell Biology 153, no. 4 (May 14, 2001): 773–84. http://dx.doi.org/10.1083/jcb.153.4.773.
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Xist RNA expression, methylation of CpG islands, and hypoacetylation of histone H4 are distinguishing features of inactive X chromatin. Here, we show that these silencing mechanisms act synergistically to maintain the inactive state. Xist RNA has been shown to be essential for initiation of X inactivation, but not required for maintenance. We have developed a system in which the reactivation frequency of individual X-linked genes can be assessed quantitatively. Using a conditional mutant Xist allele, we provide direct evidence for that loss of Xist RNA destabilizes the inactive state in somatic cells, leading to an increased reactivation frequency of an X-linked GFP transgene and of the endogenous hypoxanthine phosphoribosyl transferase (Hprt) gene in mouse embryonic fibroblasts. Demethylation of DNA, using 5-azadC or by introducing a mutation in Dnmt1, and inhibition of histone hypoacetylation using trichostatin A further increases reactivation in Xist mutant fibroblasts, indicating a synergistic interaction of X chromosome silencing mechanisms.
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Zou, Lei, Feng-Rong Chen, Ren-Pin Xia, Hua-Wei Wang, Zhen-Rong Xie, Yu Xu, Jue-Hua Yu, and Kun-Hua Wang. "Long noncoding RNA XIST regulates the EGF receptor to promote TGF-β1-induced epithelial–mesenchymal transition in pancreatic cancer." Biochemistry and Cell Biology 98, no. 2 (April 2020): 267–76. http://dx.doi.org/10.1139/bcb-2018-0274.
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Background: This study focuses on the lncRNA XIST (X inactive-specific transcript), an lncRNA involved in multiple human cancers, and investigates the functional significance of XIST and the molecular mechanisms underlying the epithelial–mesenchymal transition (EMT) in pancreatic cancer (PC). Methods: Clinical specimens from 25 patients as well as 5 human PC cell lines were analyzed for XIST, YAP, and microRNA(miR)-34a by quantitative real-time PCR (qRT-PCR) and immunohistochemistry. To investigate how XIST influences cell proliferation, invasiveness, and apoptosis in PC, we performed the CCK-8 assays, Transwell assays, and flow cytometry. Luciferase reporter assays, qRT-PCR, and Western blot were applied to prove that miR-34a directly binds to XIST. Results: Up-regulation of XIST and Yes associated protein (YAP) and down-regulation of miR-34a were consistently observed in the clinical specimens and PC cell lines. Silencing XIST reduced the expression of YAP and suppressed transforming growth factor (TGF)-β1-induced EMT, while over-expression of XIST increased the expression of YAP and promoted EMT. In addition, inhibition of epidermal growth factor receptor (EGFR) hampered the XIST-promoted EMT. The results from the luciferase reporter assays confirmed that miR-34a directly targets XIST and suggested that XIST regulates cell proliferation, invasiveness, and apoptosis in PC by sponging miR-34a. Conclusions: XIST promotes TGF-β1-induced EMT by regulating the miR-34a–YAP–EGFR axis in PC.
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Katopodis, Periklis, Qiduo Dong, Heerni Halai, Cristian I. Fratila, Andreas Polychronis, Vladimir Anikin, Cristina Sisu, and Emmanouil Karteris. "In Silico and In Vitro Analysis of lncRNA XIST Reveals a Panel of Possible Lung Cancer Regulators and a Five-Gene Diagnostic Signature." Cancers 12, no. 12 (November 24, 2020): 3499. http://dx.doi.org/10.3390/cancers12123499.
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Long non-coding RNAs (lncRNAs) perform a wide functional repertoire of roles in cell biology, ranging from RNA editing to gene regulation, as well as tumour genesis and tumour progression. The lncRNA X-inactive specific transcript (XIST) is involved in the aetiopathogenesis of non-small cell lung cancer (NSCLC). However, its role at the molecular level is not fully elucidated. The expression of XIST and co-regulated genes TSIX, hnRNPu, Bcl-2, and BRCA1 analyses in lung cancer (LC) and controls were performed in silico. Differentially expressed genes (DEGs) were determined using RNA-seq in H1975 and A549 NSCLC cell lines following siRNA for XIST. XIST exhibited sexual dimorphism, being up-regulated in females compared to males in both control and LC patient cohorts. RNA-seq revealed 944 and 751 DEGs for A549 and H1975 cell lines, respectively. These DEGs are involved in signal transduction, cell communication, energy pathways, and nucleic acid metabolism. XIST expression associated with TSIX, hnRNPu, Bcl-2, and BRCA1 provided a strong collective feature to discriminate between controls and LC, implying a diagnostic potential. There is a much more complex role for XIST in lung cancer. Further studies should concentrate on sex-specific changes and investigate the signalling pathways of the DEGs following silencing of this lncRNA.
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Sado, Takashi, and Neil Brockdorff. "Advances in understanding chromosome silencing by the long non-coding RNA Xist." Philosophical Transactions of the Royal Society B: Biological Sciences 368, no. 1609 (January 5, 2013): 20110325. http://dx.doi.org/10.1098/rstb.2011.0325.
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In female mammals, one of the two X chromosomes becomes genetically silenced to compensate for dosage imbalance of X-linked genes between XX females and XY males. X chromosome inactivation (X-inactivation) is a classical model for epigenetic gene regulation in mammals and has been studied for half a century. In the last two decades, efforts have been focused on the X inactive-specific transcript ( Xist ) locus, discovered to be the master regulator of X-inactivation. The Xist gene produces a non-coding RNA that functions as the primary switch for X-inactivation, coating the X chromosome from which it is transcribed in cis . Significant progress has been made towards understanding how Xist is regulated at the onset of X-inactivation, but our understanding of the molecular basis of silencing mediated by Xist RNA has progressed more slowly. A picture has, however, begun to emerge, and new tools and resources hold out the promise of further advances to come. Here, we provide an overview of the current state of our knowledge, what is known about Xist RNA and how it may trigger chromosome silencing.
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Xiong, Yaoyao, Long Wang, Yuan Li, Minfeng Chen, Wei He, and Lin Qi. "The Long Non-Coding RNA XIST Interacted with MiR-124 to Modulate Bladder Cancer Growth, Invasion and Migration by Targeting Androgen Receptor (AR)." Cellular Physiology and Biochemistry 43, no. 1 (2017): 405–18. http://dx.doi.org/10.1159/000480419.
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Backgrounds/Aims: Long non-coding RNA (lncRNA) X-inactive specific transcript (XIST) is involved in the progression of several tumors. The interaction between lncRNA and miRNA or miRNA’s target genes is reported to play crucial roles in malignancy. In addition, Androgen receptor (AR) is considered to be involved in bladder cancer progression. In this study, we investigated the role of XIST in human bladder cancer and its interaction with miR-124 and AR. Methods: XIST and AR expression was detected in bladder tumor samples and cell lines. Effects of XIST and AR on bladder cancer cells growth, invasion and migration were analyzed. Bioinformatic analysis and luciferase assays were used to identify the interaction among XIST, AR and miR-124. The correlations of miR-124 with XIST and AR in bladder cancer samples were statistically analyzed. Results: XIST and AR were upregulated in bladder cancer tissues and positively correlated. Higher XIST and AR expression were related to poorer TNM stage of bladder cancer. XIST knockdown reduced bladder cancer cells’ proliferation, invasion and migration. While this inhibitory effect could be partially restored by AR overexpression. XIST inhibited miR-124 expression by directly targeting. Moreover, miR-124 could bind to the 3’UTR of AR to regulate its expression. MiR-124 inhibition partially restored the XIST knockdown-induced reduction of AR, c-myc, p27, MMP13 and MMP9 expression. In bladder cancer tissues, miR-124 level was inversely correlated with the expression of XIST and AR, respectively. Conclusion: These findings indicated that XIST might be an oncogenic lncRNA that promoted the bladder cancer growth, invasion and migration via miR-124 dependent AR regulation.
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Zhong, Xueren, Yongzheng Bao, Qiang Wu, Xinhua Xi, Wengang Zhu, Sanmei Chen, and Junjian Liao. "Long noncoding RNA XIST knockdown relieves the injury of microglia cells after spinal cord injury by sponging miR-219-5p." Open Medicine 16, no. 1 (January 1, 2021): 1090–100. http://dx.doi.org/10.1515/med-2021-0292.
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Abstract Long noncoding RNAs have been demonstrated to play crucial roles in the pathogenesis of spinal cord injury (SCI). In this study, we aimed to explore the roles and underlying mechanisms of lncRNA X-inactive specific transcript (XIST) in SCI progression. SCI mice model was constructed and evaluated by the Basso–Beattie–Bresnahan method. The SCI cell model was constructed by treating BV2 cells with lipopolysaccharide (LPS). The levels of XIST and miR-219-5p were determined by the reverse transcription quantitative polymerase chain reaction. The concentrations of inflammatory cytokines were measured by enzyme-linked immunosorbent assay. Protein levels were measured via western blot assay. Cell viability and apoptosis were evaluated by cell counting kit-8 assay and flow cytometry analysis, respectively. The relationship between XIST and miR-219-5p was analyzed by online tool starBase, dual-luciferase reporter assay, and RNA immunoprecipitation assay. As a result, the XIST level was enhanced and the miR-219-5p level was declined in the SCI mice model. XIST was also upregulated in LPS-induced BV2 cells. LPS treatment restrained BV2 cell viability and accelerated apoptosis and inflammatory response. XIST knockdown effectively weakened LPS-induced BV2 cell injury. miR-219-5p was identified as a target of XIST. Moreover, inhibition of miR-219-5p restored the impacts of XIST knockdown on cell viability, apoptosis, and inflammation in LPS-treated BV2 cells. In addition, LPS-induced XIST promoted the activation of the nuclear factor-κB (NF-κB) pathway by sponging miR-219-5p. In conclusion, XIST silencing promoted microglial cell viability and repressed apoptosis and inflammation by sponging miR-219-5p, thus promoting the recovery of SCI.
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Lu, Zhipeng, Ava C. Carter, and Howard Y. Chang. "Mechanistic insights in X-chromosome inactivation." Philosophical Transactions of the Royal Society B: Biological Sciences 372, no. 1733 (September 25, 2017): 20160356. http://dx.doi.org/10.1098/rstb.2016.0356.
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X-chromosome inactivation (XCI) is a critical epigenetic mechanism for balancing gene dosage between XY males and XX females in eutherian mammals. A long non-coding RNA (lncRNA), XIST, and its associated proteins orchestrate this multi-step process, resulting in the inheritable silencing of one of the two X-chromosomes in females. The XIST RNA is large and complex, exemplifying the unique challenges associated with the structural and functional analysis of lncRNAs. Recent technological advances in the analysis of macromolecular structure and interactions have enabled us to systematically dissect the XIST ribonucleoprotein complex, which is larger than the ribosome, and its place of action, the inactive X-chromosome. These studies shed light on key mechanisms of XCI, such as XIST coating of the X-chromosome, recruitment of DNA, RNA and histone modification enzymes, and compaction and compartmentalization of the inactive X. Here, we summarize recent studies on XCI, highlight the critical contributions of new technologies and propose a unifying model for XIST function in XCI where modular domains serve as the structural and functional units in both lncRNA–protein complexes and DNA–protein complexes in chromatin. This article is part of the themed issue ‘X-chromosome inactivation: a tribute to Mary Lyon’.
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Zhu, Jia, Rui Zhang, Dongxiang Yang, Jibin Li, Xiaofei Yan, Keer Jin, Wenya Li, et al. "Knockdown of Long Non-Coding RNA XIST Inhibited Doxorubicin Resistance in Colorectal Cancer by Upregulation of miR-124 and Downregulation of SGK1." Cellular Physiology and Biochemistry 51, no. 1 (2018): 113–28. http://dx.doi.org/10.1159/000495168.
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Background/Aims: Doxorubicin (DOX) is a widely used chemotherapeutic agent for colorectal cancer (CRC). However, the acquirement of DOX resistance limits its clinical application for cancer therapy. Mounting evidence has suggested that aberrantly expressed lncRNAs contribute to drug resistance of various tumors. Our study aimed to explore the role and molecular mechanisms of lncRNA X-inactive specific transcript (XIST) in chemoresistance of CRC to DOX. Methods: The expressions of XIST, miR-124, serum and glucocorticoid-inducible kinase 1 (SGK1) mRNA in DOX-resistant CRC tissues and cells were detected by qRT-PCR or western blot analysis. DOX sensitivity was assessed by detecting IC50 value of DOX, the protein levels of P-glycoprotein (P-gp) and glutathione S-transferase-π (GST-π) and apoptosis. The interactions between XIST, miR-124 and SGK1 were confirmed by luciferase reporter assay, qRT-PCR and western blot. Xenograft tumor assay was used to verify the role of XIST in DOX resistance in CRC in vivo. Results: XIST expression was upregulated and miR-124 expression was downregulated in DOX-resistant CRC tissues and cells. Knockdown of XIST inhibited DOX resistance of CRC cells, as evidenced by the reduced IC50 value of DOX, decreased P-gp and GST-π levels and enhanced apoptosis in XIST-silenced DOX-resistant CRC cells. Additionally, XIST positively regulated SGK1 expression by interacting with miR-124 in DOX-resistant CRC cells. miR-124 suppression strikingly reversed XIST-knockdown-mediated repression on DOX resistance in DOX-resistant CRC cells. Moreover, SGK1-depletion-elicited decrease of DOX resistance was greatly restored by XIST overexpression or miR-124 inhibition in DOX-resistant CRC cells. Furthermore, XIST knockdown enhanced the anti-tumor effect of DOX in CRC in vivo. Conclusion: XIST exerted regulatory function in resistance of DOX possibly through miR-124/SGK1 axis, shedding new light on developing promising therapeutic strategy to overcome chemoresistance in CRC patients.
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Chanda, Kaushik, and Debashis Mukhopadhyay. "LncRNA Xist, X-chromosome Instability and Alzheimer’s Disease." Current Alzheimer Research 17, no. 6 (October 7, 2020): 499–507. http://dx.doi.org/10.2174/1567205017666200807185624.
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Neurodegenerative Diseases (NDD) are the major contributors to age-related causes of mental disability on a global scale. Most NDDs, like Alzheimer’s Disease (AD), are complex in nature - implying that they are multi-parametric both in terms of heterogeneous clinical outcomes and underlying molecular paradigms. Emerging evidence from high throughput genomic, transcriptomic and small RNA sequencing experiments hint at the roles of long non-coding RNAs (lncRNAs) in AD. X-inactive Specific Transcript (XIST), a component of the Xic, the X-chromosome inactivation centre, is an RNA gene on the X chromosome of the placental mammals indispensable for the X inactivation process. An extensive literature survey shows that aberrations in Xist expression and in some cases, a disruption of the Xchromosome inactivation as a whole play a significant role in AD. Considering the enormous potential of Xist as an endogenous silencing molecule, the idea of using Xist as a non-conventional chromosome silencer to treat diseases harboring chromosomal alterations is also being implemented. Comprehensive knowledge about how Xist could play such a role in AD is still elusive. In this review, we have collated the available knowledge on the possible Xist involvement and deregulation from the perspective of molecular mechanisms governing NDDs with a primary focus on Alzheimer’s disease. Possibilities of XIST mediated therapeutic intervention and linkages between XIC and preferential predisposition of females to AD have also been discussed.
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Shao, Yuefeng, Xinya Hu, and Xuejian Wu. "LncRNA X inactive-specific transcript promotes osteoclast differentiation through Tgif2 by acting as a ceRNA of miR-590-3p in a murine model." Regenerative Medicine 16, no. 7 (July 2021): 643–53. http://dx.doi.org/10.2217/rme-2020-0174.
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Aim: This study aims to investigate whether long noncoding RNA (lncRNA) X-inactive specific transcript (Xist) can regulate osteoclast differentiation in osteoporosis and the mechanism. Materials & methods: The mouse model of osteoporosis was established by ovariectomy surgery. Osteoclast differentiation from RAW264.7 cells was induced in vitro. The relationships between associated genes were assessed. Results: Xist and Tgif2 were upregulated, but miR-590-3p was downregulated in ovariectomy mouse femurs and cell models. Xist knockdown or miR-590-3p overexpression inhibited Tgif2 expression and osteoclast differentiation. Tgif2 and Xist were the targets of miR-590-3p. Increased miR-590-3p expression inhibited Tgif2 level and osteoclast differentiation, while Xist overexpression reversed these effects. Conclusion: Xist serves as a ceRNA of miR-590-3p to promote Tgif2 level; thereby, contributing to osteoclast differentiation.
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Xiao, Yaosheng, Lulin Liu, Yizhou Zheng, Wuyang Liu, and Youjia Xu. "Kaempferol attenuates the effects of XIST/miR-130a/STAT3 on inflammation and extracellular matrix degradation in osteoarthritis." Future Medicinal Chemistry 13, no. 17 (September 2021): 1451–64. http://dx.doi.org/10.4155/fmc-2021-0127.
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Aim: To investigate whether kaempferol exhibited protective effects on osteoarthritis chondrocytes by modulating the XIST/miR-130a/STAT3 axis. Methods: qRT-PCR and western blot assays were used for gene and protein determination. Dual luciferase reporter and RNA immunoprecipitation assays were employed to study the interaction between miRNA and lncRNA or genes. Results: Kaempferol decreased proinflammatory cytokine production and extracellular matrix degradation in C28/I2 cells. Additionally, kaempferol ameliorated XIST expression and enhanced miR-130a expression. XIST interacted with miR-130a, and STAT3 was identified as a target of miR-130a. Knockdown of XIST expression suppressed proinflammatory cytokine production and extracellular matrix degradation in C28/I2 cells. Overexpression of STAT3 rescued the effects of XIST knockdown. Conclusion: Kaempferol inhibited inflammation and extracellular matrix degradation by modulating the XIST/miR-130a/STAT3 axis in chondrocytes.
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Yin, Shuai, Jiayu Dou, Guifang Yang, and Fangfang Chen. "Long non-coding RNA XIST expression as a prognostic factor in human cancers: A meta-analysis." International Journal of Biological Markers 34, no. 4 (September 30, 2019): 327–33. http://dx.doi.org/10.1177/1724600819873010.
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A large number of literature has shown that high expression of X inactive-specific transcript (XIST) is associated with poor prognosis and metastasis of cancer in patients. However, most of this literature is limited by the small sample sizes and discrete outcomes. Therefore, a meta-analysis was performed to investigate the relation between XIST expression and tumor node metastasis (TNM) stage, lymph node metastasis, distant metastasis, and overall survival of cancer patients. We searched for literature in PubMed, Embase, and Web of Science. The pooled hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the association of XIST expression with prognosis and clinicopathological characteristics of cancer patients. Finally, a total of 14 articles involving 1123 patients were included in this meta-analysis. The results suggested that high expression of XIST has a significant relationship with a relatively poor overall survival for patients with malignant tumors (HR 1.82; 95% CI 1.32, 2.52; P = 0.0003). Moreover, high expression of XIST was significantly associated with poor TNM stage (OR 3.64; 95% CI 2.62, 5.07; P < 0.0001), lymph node metastasis (OR 2.39; 95% CI 1.65, 3.46; P < 0.0001) and distant metastasis (OR 2.84; 95% CI 1.90, 4.23; P < 0.0001). In conclusion, high expression of lncRNA XIST may be a predictive factor of poor prognosis in human cancers.
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Zhang, Yanfeng, Xinrui Li, Andrew Gibson, Jeffrey Edberg, Robert P. Kimberly, and Devin M. Absher. "Skewed allelic expression on X chromosome associated with aberrant expression of XIST on systemic lupus erythematosus lymphocytes." Human Molecular Genetics 29, no. 15 (July 6, 2020): 2523–34. http://dx.doi.org/10.1093/hmg/ddaa131.
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Abstract A common feature of autoimmune diseases, including systemic lupus erythematosus (SLE), is an increased prevalence in women. However, the molecular basis for sex disparity in SLE remains poorly understood. To examine the role of X-linked transcription in SLE adaptive immune cells, we performed RNA-seq in T cell and B cell subsets from either healthy donors or patients with SLE. Analyses of allelic expression (AE) profiles identified a pattern of increased allelic imbalance across the entire X chromosome in SLE lymphocytes. X-linked genes exhibiting AE in SLE had an extensive overlap with genes known to escape X chromosome inactivation (XCI). XIST RNA was overexpressed in SLE patients. Differential XIST expression correlated with AE profiles more positively at X-linked genes than the genome-wide background. Analysis of three independent RNA-seq data verified the XIST-associated skewed AE on X chromosome in SLE. Integrative analyses of DNA methylation profiles showed an increased variability of DNA methylation levels at these AE-related X-linked genes. In cultured lymphoblastic cells, knockdown of XIST specifically altered allelic imbalance patterns between X chromosomes. Our study provides genetic evidence that upregulation of XIST accompanied with more skewed allelic expression on X chromosome is associated with the pathogenesis of SLE and may provide mechanistic insights into the increased incidence of SLE in females.
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Sun, Sha, Brian C. Del Rosario, Attila Szanto, Yuya Ogawa, Yesu Jeon, and Jeannie T. Lee. "Jpx RNA Activates Xist by Evicting CTCF." Cell 153, no. 7 (June 2013): 1537–51. http://dx.doi.org/10.1016/j.cell.2013.05.028.
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Chu, Ci, Qiangfeng Cliff Zhang, Simão Teixeira da Rocha, Ryan A. Flynn, Maheetha Bharadwaj, J. Mauro Calabrese, Terry Magnuson, Edith Heard, and Howard Y. Chang. "Systematic Discovery of Xist RNA Binding Proteins." Cell 161, no. 2 (April 2015): 404–16. http://dx.doi.org/10.1016/j.cell.2015.03.025.
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Monfort, Asun, and Anton Wutz. "The B-side of Xist." F1000Research 9 (January 28, 2020): 55. http://dx.doi.org/10.12688/f1000research.21362.1.
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Female mammals express the long noncoding X inactivation-specific transcript (Xist) RNA to initiate X chromosome inactivation (XCI) that eventually results in the formation of the Barr body. Xist encompasses half a dozen repeated sequence stretches containing motifs for RNA-binding proteins that recruit effector complexes with functions for silencing genes and establishing a repressive chromatin configuration. Functional characterization of these effector proteins unveils the cooperation of a number of pathways to repress genes on the inactive X chromosome. Mechanistic insights can be extended to other noncoding RNAs with similar structure and open avenues for the design of new therapies to switch off gene expression. Here we review recent advances in the understanding of Xist and on this basis try to synthesize a model for the initiation of XCI.
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Yang, Jindou, Yan Shen, Xia Yang, Yanjun Long, Shuang Chen, Xin Lin, Rong Dong, and Jing Yuan. "Silencing of long noncoding RNA XIST protects against renal interstitial fibrosis in diabetic nephropathy via microRNA-93-5p-mediated inhibition of CDKN1A." American Journal of Physiology-Renal Physiology 317, no. 5 (November 1, 2019): F1350—F1358. http://dx.doi.org/10.1152/ajprenal.00254.2019.
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Long noncoding RNAs (lncRNAs) have been reported to play an important role in diabetic nephropathy (DN). However, the molecular mechanism involved in this process remains poorly understood. Thus, the present study aimed to explore the function and molecular mechanism of dysregulated lncRNA X-inactive specific transcript (XIST) in DN. DN mouse models were established by streptozotocin treatment, and human renal tubular epithelial HK-2 cells were exposed to high glucose to produce an in vitro model. XIST was highly expressed in renal tissues of patients with DN, mice with DN, and high glucose-exposed HK-2 cells. To identify the interaction among XIST, miR-93-5p, and cyclin-dependent kinase inhibitor 1A (CDKN1A) and to analyze the functional significance of their interaction in renal interstitial fibrosis, we altered endogenous expression of XIST and miR-93-5p and CDKN1A. Dual-luciferase reporter assay results suggested that XIST was highly expressed in the kidney tissue of DN mice and high glucose-exposed HK-2 cells. XIST was identified to be a lncRNA that could bind to miR-93-5p, and CDKN1A was a target of miR-93-5p. Downregulated expression of XIST led to an increase in miR-93-5p expression, thereby decreasing CDKN1A and suppressing renal interstitial fibrosis in DN. Consistently, XIST knockdown reduced the expression of fibrosis markers (fibronectin, collagen type IV, and transforming growth factor-β1). Restoration of CDKN1A or decreasing miR-93-5p yielded a reversed effect on renal interstitial fibrosis. In conclusion, our study demonstrated that silenced XIST inducing miR-93-5p-dependent CDKN1A inhibition was beneficial for preventing renal interstitial fibrosis in DN, which may provide a future strategy to prevent the progression of DN.
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Hall, Lisa L., and Jeanne B. Lawrence. "The cell biology of a novel chromosomal RNA: chromosome painting by XIST/Xist RNA initiates a remodeling cascade." Seminars in Cell & Developmental Biology 14, no. 6 (December 2003): 369–78. http://dx.doi.org/10.1016/j.semcdb.2003.09.011.
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Savarese, Fabio, Katja Flahndorfer, Rudolf Jaenisch, Meinrad Busslinger, and Anton Wutz. "Hematopoietic Precursor Cells Transiently Reestablish Permissiveness for XInactivation." Molecular and Cellular Biology 26, no. 19 (October 1, 2006): 7167–77. http://dx.doi.org/10.1128/mcb.00810-06.
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ABSTRACT Xist is the trigger for X inactivation in female mammals. The long noncoding Xist RNA localizes along one of the two female X chromosomes and initiates chromosome-wide silencing in the early embryo. In differentiated cells, Xist becomes dispensable for the maintenance of the inactive X, and its function for initiation of silencing is lost. How Xist mediates gene repression remains an open question. Here, we use an inducible Xist allele in adult mice to identify cells in which Xist can cause chromosome-wide silencing. We show that Xist has the ability to initiate silencing in immature hematopoietic precursor cells. In contrast, hematopoietic stem cells and mature blood cells are unable to initiate ectopic X inactivation. This indicates that pathways critical for silencing are transiently activated in hematopoietic differentiation. Xist-responsive cell types in normal female mice show a change of chromatin marks on the inactive X. However, dosage compensation is maintained throughout hematopoiesis. Therefore, Xist can initiate silencing in precursors with concomitant maintenance of dosage compensation. This suggests that Xist function is restricted in development by the limited activity of epigenetic pathways rather than by a change in the responsiveness of chromatin between embryonic and differentiated cell types.
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Sado, Takashi. "What makes the maternal X chromosome resistant to undergoing imprinted X inactivation?" Philosophical Transactions of the Royal Society B: Biological Sciences 372, no. 1733 (September 25, 2017): 20160365. http://dx.doi.org/10.1098/rstb.2016.0365.
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In the mouse, while either X chromosome is chosen for inactivation in a random fashion in the embryonic tissue, the paternally derived X chromosome is preferentially inactivated in the extraembryonic tissues. It has been shown that the maternal X chromosome is imprinted so as not to undergo inactivation in the extraembryonic tissues. X-linked noncoding Xist RNA becomes upregulated on the X chromosome that is to be inactivated. An antisense noncoding RNA, Tsix , which occurs at the Xist locus and has been shown to negatively regulate Xist expression in cis, is imprinted to be expressed from the maternal X in the extraembryonic tissues. Although Tsix appears to be responsible for the imprint laid on the maternal X, those who disagree with this idea would point out the fact that Tsix has not yet been expressed from the maternal X when Xist becomes upregulated on the paternal but not the maternal X at the onset of imprinted X-inactivation in preimplantation embryos. Recent studies have demonstrated, however, that there is a prominent difference in the chromatin structure at the Xist locus depending on the parental origin, which I suggest might account for the repression of maternal Xist in the absence of maternal Tsix at the preimplantation stages. This article is part of the themed issue ‘X-chromosome inactivation: a tribute to Mary Lyon’.
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Chen, Shenglan, Ai Jiang, Yan Wang, and Yina Wang. "Long Non-Coding RNA X Inactive Specific Transcript Suppressed the Proliferation and Invasion of Ovarian Cancer Cells by Restricting the Expression of Staphylococcal Nuclease Domain Containing 1." Journal of Biomaterials and Tissue Engineering 10, no. 12 (December 1, 2020): 1793–99. http://dx.doi.org/10.1166/jbt.2020.2490.
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Ovarian cancer is one kind of a deadly gynecological malignancy. Recent study has shown that SND1 was associated with the development of ovarian cancer. Furthermore, the expression of lncRNA XIST in ovarian cancer was down-regulated. However, it is unclear whether lncRNA XIST could affect the occurrence and development of ovarian cancer by targeting SND1. In this study, we used the lentivirus to establish the overexpression and knockdown SND1 ovarian cancer cells. And we next detected the proliferation and invasion of these cells in diverse groups. Then, the luciferase assays were performed to detect the targeted effect of lncRNA XIST on SND1 and determined the expression of SND1 in the overexpressed lncRNA XIST ovarian cancer cells. We found that SND1 promoted the proliferation and invasion of ovarian cancer cells. And the lncRNA XIST targeted and suppressed the expression of SND1. Overexpression of lncRNA XIST inhibited the proliferation and invasion of ovarian cancer cells. However, the overexpression of SND1 alleviated the inhibitory efficacy of lncRNA XIST on the proliferation and invasion of ovarian cancer cells. LncRNA XIST inhibited the proliferation and invasion of ovarian cancer by suppressing the expression of SND1.
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Wang, Jinglu, Haibo Cai, Zhaoxia Dai, and Gang Wang. "Down-regulation of lncRNA XIST inhibits cell proliferation via regulating miR-744/RING1 axis in non-small cell lung cancer." Clinical Science 133, no. 14 (July 2019): 1567–79. http://dx.doi.org/10.1042/cs20190519.
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Abstract Long non-coding RNAs (lncRNAs) are known to be potential factors in promoting tumor progression. However, the function and mechanism of lncRNA XIST in non-small cell lung cancer (NSCLC) remains poorly understood. The expression levels of lncRNA XIST in NSCLC tissues and cell lines were detected with real-time PCR, and the correlation of the expression level of XIST with histopathological characteristics and prognosis was analyzed. The biological function of lncRNA XIST was validated through assays in vivo and in vitro. The expression of lncRNA XIST was significantly up-regulated in NSCLC tissues. In addition, overexpression of XIST was positively correlated with the advanced clinical status of tumors, as well as poor overall survival and DFS. A tumor suppressive effect was presented via functional knockdown of lncRNA XIST. Up-regulation of XIST enhanced the proliferation, migration, and invasion ability of NSCLC cells both in vivo and in vitro. Mechanically, it was indicated that XIST could serve as an endogenous competitive RNA modulating miR-744, leading to the miR-744/RING1 signaling pathway inhibition and Wnt/β-catenin signaling pathway activation. Taken together, it was confirmed here that XIST overexpression is associated with tumor progression phenotype and the newly discovered XIST/miR-744/RING1 axis, which could serve as a potential biomarker and therapeutic target for NSCLC.
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Ganesan, Shridar, Daniel P. Silver, Ronny Drapkin, Roger Greenberg, Jean Feunteun, and David M. Livingston. "Association of BRCA1 with the inactive X chromosome and XIST RNA." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 359, no. 1441 (January 29, 2004): 123–28. http://dx.doi.org/10.1098/rstb.2003.1371.
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Breast cancer, early onset 1 (BRCA1) encodes a nuclear protein that participates in breast and ovarian cancer suppression. The molecular basis for the gender and tissue specificity of the BRCA1 cancer syndrome is unknown. Recently, we observed that a fraction of BRCA1 in female cells is localized on the inactive X chromosome (Xi). Chromatin immunoprecipitation (ChIP) experiments have demonstrated that BRCA1 physically associates with Xi–specific transcript (XIST) RNA, a non–coding RNA known to coat Xi and to participate in the initiation of its inactivation during early embryogenesis. Cells lacking wild–type BRCA1 show abnormalities in Xi, including lack of proper XIST RNA localization. Reintroduction of wild–type, but not mutant, BRCA1 can correct this defect in XIST localization in these cells. Depletion of BRCA1 in female diploid cells led to a defect in proper XIST localization on Xi and in the development of normal Xi heterchromatic superstructure. Moreover, depletion of BRCA1 led to an increased likelihood of re–expression of a green fluorescent protein (GFP) reporter gene embedded on Xi. Taken together, these findings are consistent with a model in which BRCA1 function contributes to the maintenance of proper Xi heterochromatin superstructure. Although the data imply a novel gender–specific consequence of BRCA1 loss, the relevance of the BRCA1/Xi function to the tumour suppressor activity of BRCA1 remains unclear and needs to be tested.