A Primary Role for the Tsix lncRNA in Maintaining Random X-Chromosome Inactivation

Gayen, Srimonta; Maclary, Emily; Buttigieg, Emily; Hinten, Michael; Kalantry, Sundeep

doi:10.1016/j.celrep.2015.04.039

Cited by 81 publications

(126 citation statements)

References 54 publications

(98 reference statements)

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“…Strong Xist RNA-decorated X ΔTsix Y nuclei reached a maximum of between 40% and 58% of all nuclei at day 6 (d6) of differentiation, before decreasing to ∼30% at d10 (Fig. 1A) upon differentiation (6,30,32 X nuclei exhibited one strong and one weak Xist RNA-coated X chromosome, with a maximum of 4%. By d10, double Xist RNA-coated X ΔTsix X nuclei had rapidly declined and disappeared altogether (Fig.…”

Section: Significancementioning

confidence: 99%

“…mutant allele) (30,31). We assessed ectopic Xist RNA coating every 2 d over a period of 10 d by RNA fluorescence in situ hybridization (FISH).…”

Section: Significancementioning

confidence: 99%

“…We surmised that the difference in the frequency and the kinetics of ectopic Xist RNA-coated nuclei between male X ΔTsix Y and female X ΔTsix X ESC lines may reflect variable silencing of X-linked genes between the sexes. Functional nullizygosity of X-linked genes is expected to be deleterious, leading to selection against these cells (30,33). Thus, the higher steady-state percentage of X ΔTsix Y nuclei with Xist RNA coating may reflect inefficient silencing of X-linked genes upon ectopic Xist RNA coating in mutant males compared with females.…”

Section: Significancementioning

confidence: 99%

“…1A). We previously showed that the second Xist-decorated X chromosome in differentiating X ΔTsix X ESCs is the X ΔTsix mutant X chromosome (30). Xist is therefore ectopically induced from the X ΔTsix in females, as it is in males.…”

Section: Significancementioning

confidence: 99%

“…We previously generated male and female embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs) that harbor an X chromosome with a null mutation in the Xist antisense repressor Tsix (X ΔTsix ) (30). A subset of differentiating X ΔTsix Y and X ΔTsix X cells display ectopic Xist RNA coating of the X ΔTsix ; thus, male cells harbor a single Xist RNA coat and females possess two Xist coats.…”

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confidence: 99%

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Sex-specific silencing of X-linked genes by Xist RNA

Gayen

Maclary

Hinten

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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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 X ΔTsix Y male cells displayed ectopic Xist RNA coating compared with X ΔTsix X female cells. This increase reflected the inability of X ΔTsix Y cells to efficiently silence X-linked genes compared with X ΔTsix X cells, despite equivalent Xist RNA induction and coating. Silencing of genes on both Xs resulted in significantly reduced proliferation and increased cell death in X ΔTsix X female cells relative to X ΔTsix Y 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 X ΔTsix Y and 39,X ΔTsix (X ΔTsix O) ESCs, excluding the Y chromosome and instead implicating the X-chromosome dose as the source of the sexspecific differences. Because X ΔTsix X female embryonic epiblast cells and EpiSCs harbor an inactivated X chromosome prior to ectopic inactivation of the active X ΔTsix 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.inactivation represents a paradigm of epigenetic regulation and long noncoding RNA (lncRNA) function. In XX female cells, one of the two X chromosomes undergoes transcriptional silencing (1). Moreover, replicated copies of the active and inactive X chromosomes faithfully maintain their respective transcriptional states through many cell division cycles (2-5).X inactivation requires the X-inactive specific transcript (Xist) (6-8), a lncRNA that is selectively expressed from and physically coats the future inactive X chromosome (9-12). Xist RNA enables X-linked gene silencing by recruiting protein complexes to the inactive X (13-15). Female mouse embryos that inherit a paternal Xist mutation die due to defects in imprinted X inactivation of the paternal X chromosome in extraembryonic tissues (8,16,17). Xist is also required in the epiblast-derived embryonic cells, which undergo random X inactivation of either the maternal or the paternal X chromosome. Xist heterozygote fetal cells exhibit inactivation of only the X chromosome with an intact Xist locus, suggesting that Xist is necessary to choose the X chromosome to be inactivated (7,18,19). That the Xist-mutant X chromosome is not selected for inactivation, however, precludes assigning to Xist RNA a gene silencing role in the epiblast lineage.Ectopic expression studies have, however, demonstrated that Xist RNA can silence genes, albeit in a context-...

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Section: Significancementioning

confidence: 99%

“…mutant allele) (30,31). We assessed ectopic Xist RNA coating every 2 d over a period of 10 d by RNA fluorescence in situ hybridization (FISH).…”

Section: Significancementioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Section: Significancementioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Sex-specific silencing of X-linked genes by Xist RNA

Gayen

Maclary

Hinten

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Long noncoding RNAs in autoimmune diseases

Lei

Jin

et al. 2018

J Biomedical Materials Res

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With the completion of the human genome project and further development of high‐throughput genomic technologies, interest in long noncoding RNAs (lncRNAs), which are defined as non‐protein‐coding RNAs at least 200 nucleotides in length, has strongly increased, and lncRNAs have become a major research direction. Increasing evidence demonstrates that lncRNAs are closely related to human growth and development and to disease occurrence via various mechanisms. lncRNAs also play crucial roles in the differentiation and activation of immune cells, and their relationships with human autoimmune diseases have received increasing attention. The development of biotechnology has led to the gradual discovery of many potential lncRNA functions. In this review, we discuss various lncRNAs that have been implicated in different human autoimmune diseases, focusing on their clinical applications as potential biomarkers and therapeutic targets in the pathologies of diverse human autoimmune diseases. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 468–475, 2019.

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LncRNA XIST facilitates proliferation and epithelial–mesenchymal transition of colorectal cancer cells through targeting miR‐486‐5p and promoting neuropilin‐2

Liu

Lü

2019

Journal Cellular Physiology

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This study was designed to acertain whether the long noncoding RNA (lncRNA) X‐inactive specific transcript (XIST)/miR‐486‐5p/neuropilin‐2 (NRP‐2) pathway might promote the viability and epithelial–mesenchymal transition (EMT) of colorectal cancer (CRC) cells. In this investigation, we included 317 pathologically confirmed CRC patients and purchased several human CRC cells (i.e. HCT116, HT29, SW620, and SW480). Moreover, pcDNA3.1‐XIST, si‐XIST, miR‐486‐5p mimic, miR‐486‐5p inhibitor, and pcDNA3.1‐NRP‐2 were transfected into the CRC cells. And the dual‐luciferase reporter gene assay managed to verify the targeted relationships among XIST, miR‐486‐5p, and NRP‐2. Ultimately, the MTT assay, flow cytometry, colony formation assay, and transwell assay were carried out to assess the influence of XIST, miR‐486‐5p, and NRP‐2 on the proliferation, apoptosis, migration, and invasion of CRC cells. Our study results demonstrated that CRC tissues and cells were detected with significantly elevated XIST and NRP‐2 expressions as well as markedly reduced miR‐486‐5p expression when compared with normal tissues and cells (all p < 0.05). Besides this, the highly expressed XIST and NRP‐2, as well as the lowly expressed miR‐486‐5p all could substantially encourage proliferation and EMT of CRC cells and simultaneously restrict apoptosis of the cells ( p < 0.05). Moreover, XIST was found to directly target miR‐486‐5p, and NRP‐2 was directly targeted and modulated by miR‐486‐5p. Finally, CRC cells of the miR‐NC + pcDNA3.1‐NRP‐2 groups showed stronger proliferation, viability, and EMT than those of miR‐NC and miR‐486‐5p mimic groups ( p < 0.05). In conclusion, the XIST/miR‐486 ‐5p/NRP‐2 axis appeared to participate in the progression of CRC, which could assist in developing efficacious therapies for CRC.

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A Primary Role for the Tsix lncRNA in Maintaining Random X-Chromosome Inactivation

Cited by 81 publications

References 54 publications

Sex-specific silencing of X-linked genes by Xist RNA

Sex-specific silencing of X-linked genes by Xist RNA

Long noncoding RNAs in autoimmune diseases

LncRNA XIST facilitates proliferation and epithelial–mesenchymal transition of colorectal cancer cells through targeting miR‐486‐5p and promoting neuropilin‐2

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