Comprehensive multi-omics analysis uncovers a group of TGF-β-regulated genes among lncRNA EPR direct transcriptional targets

Zapparoli, Ettore; Briata, Paola; Rossi, Martina; Brondolo, Lorenzo; Bucci, Gabriele; Gherzi, Roberto

doi:10.1093/nar/gkaa628

Cited by 16 publications

(7 citation statements)

References 44 publications

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“…Undoubtedly, additional modes of action for LINC00313 cannot be excluded. For example, nuclear lncRNAs frequently form triplex formation with DNA at chromatin regions, through direct base pairing [37]. It is worth to investigate whether LINC00313 participates in these loops, in order to alter chromatin accessibility.…”

Section: Discussionmentioning

confidence: 99%

TGFβ-induced long non-coding RNA LINC00313 activates Wnt signalling and promotes cholangiocarcinoma progression

Papoutsoglou

Louis

Pineau

et al. 2022

Preprint

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Background: Cholangiocarcinoma (CCA) is a devastating liver cancer characterized by high aggressiveness and resistance to therapy, which results to poor prognosis. Long non-coding RNAs (lncRNAs) and signals imposed by oncogenic pathways, such as transforming growth factor β (TGFβ) frequently contribute to CCA development. Here, we explored novel effectors of TGFβ signalling in CCA.Methods: We performed gene expression profiling to identify TGFβ-regulated genes in CCA cell lines. RNA-sequencing and ATAC-sequencing after LINC00313 gain-of-function were used to identify transcriptional targets of LINC00313, in vitro. We evaluated the impact of LINC00313 on TCF/LEF signalling by luciferase assays. Mouse xenograft models were used to evaluate the effects of LINC00313 on CCA progression, in vivo. Integrative analysis revealed the clinical relevance of LINC00313 in CCA. We identified LINC00313-interacting proteins by RNA-pull down, followed by mass spectrometry.Results: LINC00313 was identified as a novel target of TGFβ signalling in CCA cells. TGFβ induced LINC00313 expression in a TβRI/Smad-dependent manner. LINC00313 regulated genes involved in Wnt signalling. LINC00313 gain-of-function increased TCF7 expression. Of note, LINC00313 enhanced TCF/LEF-dependent transcriptional responses, promoted colony-forming capacities of CCA cells in vitro and accelerated tumour growth in vivo. Genes associated with LINC00313 over-expression in CCA tumours were characterized by KRAS and TP53 mutations and reduced patient’s overall survival. Mechanistically, actin-like 6A (ACTL6A), a subunit of the SWI/SNF chromatin remodelling complex, interacted with LINC00313 and impacted on TCF7 and SULF2 transcription and TCF/LEF signalling output.Conclusions: We propose a model whereby TGFβ induces LINC00313 in order to regulate expression of a subset of target genes, possibly in co-operation with SWI/SNF. By regulating key genes of the Wnt pathway, LINC00313 fine-tunes Wnt/TCF/LEF-dependent transcriptional responses and boosts cholangiocarcinogenesis.

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Section: Discussionmentioning

confidence: 99%

TGFβ-induced long non-coding RNA LINC00313 activates Wnt signalling and promotes cholangiocarcinoma progression

Papoutsoglou

Louis

Pineau

et al. 2022

Preprint

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“…In RNABSdb we have 20 human and murine lncRNAs with publicly available RNABS-seq data, but without experimental evidence of functional TPX. For two of them, the authors tested the capability of forming TPXs in silico (AC087482.1, Eprn) (10,33) and for Tug1 (34), the TPX mechanism of binding was only speculated.…”

Section: Evidence Of Tpx Potential For Many Lncrnamentioning

confidence: 99%

“…Some lncRNAs are known to regulate gene expression of specific target genes through binding to specific TTS in their DNA regulatory regions, acting analogously to transcription factors. For example, the murine lncRNA EPR binds on Arrdc3 promoter, thus activating its expression and modulating the epithelial to mesenchymal transition (10). Similarly, LncSmad7 binds and recruits p300 to enhancer regions in trans , triggering their acetylation and transcriptional activation of their target genes, controlling the expression of key stemness regulators (11).…”

Section: Introductionmentioning

confidence: 99%

RNABSdb and 3plex enable deep computational investigation of triplex forming lncRNAs

Cicconetti

Lauria

Proserpio

et al. 2022

Preprint

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1.AbstractLong non-coding RNAs (lncRNAs) regulate gene expression through different molecular mechanisms, including DNA binding. We curated a database of RNA Binding Sites (RNABSdb) by harmonising publicly available raw-data of RNA-DNA binding. This resource is required to enable systematic studies on transcriptional regulation driven by lncRNAs. Focusing on high quality experiments, we found that the number of binding sites for each lncRNAs varies from hundreds to tens of thousands. Despite being poorly characterised, the formation of RNA:DNA:DNA triple helices (TPXs) is one of the molecular mechanisms that allow lncRNAs to bind the genome and drive alteration of gene expression. Few computational methods exist which can predict TPXs in silico and, in this study, we developed 3plex, a software that improves the state-of-the-art TPXs prediction method. Leveraging the data collected in RNABSdb for lncRNAs known to form funcional TPXs, we showed that 3plex outperformed existing approaches. Our analysis showed that TPXs tend to be shorter and more degenerated than expected. Finally, we applied 3plex to all the lncRNAs collected in RNABSdb and we show that the majority of lncRNA could bind the genome by TPXs formation.Data and software are available at https://molinerislab.github.io/RNABSdb/.

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“…Alternatively, lncRNA Epr changes Cdkn1a gene expression by affecting both its transcription and mRNA decay through its association with the transcription factor SMAD3 or the RBP KHSRP, respectively. KHSRP is predominantly an mRNA decay promoting factor in epithelial cells and the interaction with Epr blocks its ability to induce decay of Cdkn1a mRNA [ 107 , 108 ].…”

Section: Interaction Between Lncrnas and Rbps In Mrna Stabilizatiomentioning

confidence: 99%

The Role of lncRNAs in Gene Expression Regulation through mRNA Stabilization

Sebastian-delaCruz

González-Moro

Olazagoitia-Garmendia

et al. 2021

ncRNA

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mRNA stability influences gene expression and translation in almost all living organisms, and the levels of mRNA molecules in the cell are determined by a balance between production and decay. Maintaining an accurate balance is crucial for the correct function of a wide variety of biological processes and to maintain an appropriate cellular homeostasis. Long non-coding RNAs (lncRNAs) have been shown to participate in the regulation of gene expression through different molecular mechanisms, including mRNA stabilization. In this review we provide an overview on the molecular mechanisms by which lncRNAs modulate mRNA stability and decay. We focus on how lncRNAs interact with RNA binding proteins and microRNAs to avoid mRNA degradation, and also on how lncRNAs modulate epitranscriptomic marks that directly impact on mRNA stability.

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Comprehensive multi-omics analysis uncovers a group of TGF-β-regulated genes among lncRNA EPR direct transcriptional targets

Cited by 16 publications

References 44 publications

TGFβ-induced long non-coding RNA LINC00313 activates Wnt signalling and promotes cholangiocarcinoma progression

TGFβ-induced long non-coding RNA LINC00313 activates Wnt signalling and promotes cholangiocarcinoma progression

RNABSdb and 3plex enable deep computational investigation of triplex forming lncRNAs

The Role of lncRNAs in Gene Expression Regulation through mRNA Stabilization

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