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The human lncRNA LINC-PINT inhibits tumor cell migration through a highly conserved sequence element

ABSTRACT: It is now obvious that the majority of cellular transcripts do not code for proteins, and a significant subset of them are long noncoding RNAs (lncRNAs). Many lncRNAs show aberrant expression in cancer, and some of them have been linked to cellular transformation. However, the underlying mechanisms remain poorly understood. Here we characterize the function of the p53-regulated human lncRNA LINC-PINT in cancer. We found that LINC-PINT acts as tumor suppressor lncRNA. Its expression is downregulated in multiple types of cancer and correlates with good prognosis in lung adenocarcinoma. LINC-PINT inhibits the migration capacity and invasive phenotype of cancer cells in vitro and in vivo, and it does so by repressing a proinvasion gene signature in a PRC2-dependent manner. By applying cross-species conservation analysis combined with functional experimental validations we found that the function of LINC-PINT is highly dependent on a short sequence conserved across mammals, sequence that mediates the interaction with PRC2. We propose that LINC-PINT may function as a molecular exchanger that provides PRC2 to active gene promoters for their silencing, mechanisms that could be shared by other PRC2-interacting lncRNAs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE98928 | GEO | 2017/09/27

SECONDARY ACCESSION(S): PRJNA386883

REPOSITORIES: GEO

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Next generation sequencing reveals upregulation of the lncRNA LINC-PINT in the substantia nigra of human Parkinson's disease patients compared to control donors

Project description:Parkinson's disease (PD) is the second most common neurodegenerative disease, involving the selecive death of dopaminergic neurons in the substantia nigra pars compacta brain region. Here, we performed next generation sequencing on RNA extracted from human substantia nigra tissue. The samples, acquired from the Netherland's Brain Bank, were taken post-mortem from PD and non-PD control donors. Analysis of the data revealed an upregulation of lncRNA LINC-PINT in PD substantia nigra. LINC-PINT interracts with the Polycomb Repressive Complex 2 (PRC2), inhibiting the tracription of multiple targets. Correspondingly, analysis of the data revealed that targets of PRC2 displayed larger disease-associated differences as compared to other genes, as well as enrichment for downregulation, suggesting that the differential expression of LINC-PINT in PD effects LINC-PINT/PRC2 interaction as well.

2020-04-14 | GSE114517 | GEO

TWIST1 methylation by SETD6 selectively antagonizes LINC-PINT expression in Glioblastoma multiforme

Project description:Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor among adults, which is characterized by high invasion, migration and proliferation abilities. One important process that contributes to the invasiveness of GBM is the epithelial to mesenchymal transition (EMT). EMT is regulated by a set of defined transcription factors which tightly regulate this process, among them is the basic helix-loop-helix family member, TWIST1. Here we show that TWIST1 is methylated on lysine-33 at chromatin by SETD6, a methyltransferase with expression levels correlating with poor survival in GBM patients. RNA-seq analysis in U251 GBM cells suggested that both SETD6 and TWIST1 regulate cell adhesion and migration processes. We further show that TWIST1 methylation attenuates the expression of the long-non-coding RNA, LINC-PINT, thereby suppressing EMT in GBM. Mechanistically, TWIST1 methylation represses the transcription of LINC-PINT by increasing the occupancy of EZH2 and the catalysis of the repressive H3K27me3 mark at the LINC-PINT locus. Under un-methylated conditions, TWIST1 dissociates from the LINC-PINT locus, allowing the expression of LINC-PINT which leads to increased cell adhesion and decreased cell migration. Together, our findings unravel a new mechanistic dimension for selective expression of LINC-PINT mediated by TWIST1 methylation.

2022-08-12 | PXD029361 | Pride

PINT lincRNA connects the p53 pathway with epigenetic silencing by the Polycomb Repressive Complex 2 (tissue)

Project description:It has been recently shown that the transcription factor p53 induces the expression of multiple lincRNAs. However, relatively little is known about the role that lincRNAs play in this pathway. Here we characterize a lincRNA named PINT (p53 Induced Noncoding Transcript). We show that PINT is a ubiquitously expressed lincRNA that is finely regulated by p53. In mouse cells, PINT promotes cell proliferation and survival by regulating the expression of genes of TGF-beta, MAPK and p53 pathways. PINT is a nuclear lincRNA that directly interacts with Polycomb Repressive Complex 2 (PRC2), being required for PRC2 targeting of specific genes for repression. Furthermore, PINT functional activity is dependent on PRC2 expression, representing a connection between the p53 pathway and epigenetic regulation by PRC2. We have also identified PINT human ortholog (hPINT), which presents suggestive analogies with the mouse lincRNA. hPINT is similarly regulated by p53, and its expression correlates significantly with the same cellular pathways as the mouse ortholog, including the p53 pathway. Interestingly, hPINT is significantly downregulated in colon cancer, representing a novel tumor suppressor candidate. Our results not only help our understanding of the role of p53 and lincRNAs in cancer, but also contribute to the open debate regarding the utility of mouse models for the study of lincRNAs. Normal tissue located at least 20 cm away from a tumor was obtained through surgical resection from patients of colorectal cancer. Total RNA was extracted and subjected to microarray analysis.

2013-08-09 | E-GEOD-46271 | biostudies-arrayexpress

PINT lincRNA connects the p53 pathway with epigenetic silencing by the Polycomb Repressive Complex 2 (MEF cells)

Project description:It has been recently shown that the transcription factor p53 induces the expression of multiple lincRNAs. However, relatively little is known about the role that lincRNAs play in this pathway. Here we characterize a lincRNA named PINT (p53 Induced Noncoding Transcript). We show that PINT is a ubiquitously expressed lincRNA that is finely regulated by p53. In mouse cells, PINT promotes cell proliferation and survival by regulating the expression of genes of TGF-beta, MAPK and p53 pathways. PINT is a nuclear lincRNA that directly interacts with Polycomb Repressive Complex 2 (PRC2), being required for PRC2 targeting of specific genes for repression. Furthermore, PINT functional activity is dependent on PRC2 expression, representing a connection between the p53 pathway and epigenetic regulation by PRC2. We have also identified PINT human ortholog (hPINT), which presents suggestive analogies with the mouse lincRNA. hPINT is similarly regulated by p53, and its expression correlates significantly with the same cellular pathways as the mouse ortholog, including the p53 pathway. Interestingly, hPINT is significantly downregulated in colon cancer, representing a novel tumor suppressor candidate. Our results not only help our understanding of the role of p53 and lincRNAs in cancer, but also contribute to the open debate regarding the utility of mouse models for the study of lincRNAs. Inhibition of PINT or p53 gene expression and subsequent treatment with 150 nM doxorubicine for 12h in MEF LSL p53 +/+ cells.

2013-08-09 | E-GEOD-46247 | biostudies-arrayexpress

Natural circular RNA encodes regulatory small peptides in Mammalian cells

Project description:To test the hypothesis that circRNAs might encode functional peptides in mammalian cells, we studied the long intergenic non-protein coding RNA, p53 induced transcript (LINC-PINT), which was previously reported as a tumor suppressor and connected p53 activation with polycomb repressive complex 2 (PRC2). We selected this long noncoding RNA (lncRNA) for further analysis because LINC-PINT has a long exon 2 which in accordance with the bioinformatical analyzed circular RNA standard.The following immunoblotting showed 87aa peptide level also decreased, indicating that this peptide is encoded by circPINTexon2. We name this circRNA encoded peptide PINT87aa. To investigate the possible regulatory role of PINT87aa, we did the expression micro array in PINT87aa stably transfect U251 or U87 glioblastoma cells and their control cells. The array analysis reveals that PINT87aa may involve in the cell cycle regulation, anti-apoptosis effects and multiple oncogenic signaling pathway activation.

2015-11-04 | E-GEOD-74610 | biostudies-arrayexpress

Natural circular RNA encodes regulatory small peptides in Mammalian cells

2015-11-04 | GSE74610 | GEO

PINT lincRNA connects the p53 pathway with epigenetic silencing by the Polycomb Repressive Complex 2 (tissue)

2013-08-09 | GSE46271 | GEO

PINT lincRNA connects the p53 pathway with epigenetic silencing by the Polycomb Repressive Complex 2 (MEF cells)

2013-08-09 | GSE46247 | GEO

An NF-κB-responsive long noncoding RNA, PINT, regulates inflammatory gene transcription by scaffolding p65 and EZH2

Project description:Long non-coding RNAs (lncRNAs) are central regulators of the inflammatory response and play an important role in inflammatory diseases. PINT has been reported to be involved in tissue development and tumorigenesis. However, potential functions of PINT in the innate immune system are largely unknown. Here, we report a specific role for PINT in activating inflammatory gene transcription. The expression of PINT is primarily dependent on the NF-κB signaling pathway in macrophages and intestinal epithelial cells. Functionally, PINT selectively promotes the expression of inflammatory genes, including TNF-α, in basal and LPS-stimulated cells. Mechanistically, PINT acts as a modular scaffold of p65 and EZH2 to coordinate their localization and specify their binding to the target genes. Further, a high expression of PINT is detected in the intestinal tissue from patients with Inflammatory Bowel Disease (IBD). Together, these findings demonstrate that PINT acts as an activator of inflammatory responses, highlighting the importance of this lncRNA in inflammatory diseases as a potential therapeutic target.

2022-10-01 | GSE139278 | GEO

Linc-smad7 promotes myoblast differentiation and muscle regeneration via sponging miR-125b

Project description:Long noncoding RNAs (lncRNAs) are involved in the regulation of skeletal muscle development. In the present study, differentially expressed lncRNAs were identified from RNA-seq data derived from myoblasts and myotubes. We conducted studies to elucidate the function and molecular mechanism of action of Linc-smad7 during skeletal muscle development. Our findings show that Linc-smad7 is upregulated during the early phase of myoblasts differentiation. In in vitro studies, we showed that overexpression of Linc-smad7 promoted the arrest of myoblasts in G1 phase, inhibited DNA replication, and induced myoblast differentiation. Our in vivo studies suggest that Linc-smad7 stimulates skeletal muscle regeneration in cardiotoxin-induced muscle injury. Mechanistically, Linc-smad7 overexpression increased smad7 and IGF2 protein levels. On the contrary, overexpression of miR-125b reduced smad7 and IGF2 protein levels. Results of RNA immunoprecipitation analysis and biotin-labeled miR-125b capture suggest that Linc-smad7 could act as a competing endogenous RNA (ceRNA) for miRNA-125b. Taken together, our findings suggest that the novel noncoding regulator Linc-smad7 regulates skeletal muscle development.

2017-11-01 | GSE106365 | GEO

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