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TGF-beta-upregulated Lnc-Nr6a1 acts as a reservoir of miR-181 and mediates assembly of a glycolytic complex [ChIP-seq]

ABSTRACT: Long noncoding RNAs (lncRNAs) have emerged as key regulators in a wide range of biological processes. The involvement of lncRNAs in epithelial-to-mesenchymal transition (EMT) has been well stablished; however, the role as immediate-early regulators is still unclear. Here, we identified a mouse miRNA-host gene lncRNA (lnc-Nr6a1) early upregulated during EMT. We show that this lncRNA is processed giving rise to abundant polyadenylated isoforms, lnc-Nr6a1 and lnc-Nr6a1-2, and a longer non-polyadenylated microprocessor-driven lnc-pri-miRNAS containing clustered pre-miRNA-181a2 and pre-miRNA-181b2 hairpins. Ectopic expression of lnc-Nr6a1-1/2 isoforms enhance cell migration and invasive capacity of the cells, whereas the expression of isoforms and miR-181a2/b2 confers anoikis resistance. Lnc-Nr6a1 gene deletion results in cells with lower adhesion capacity and reduced glycolytic metabolism which are restored by lnc-Nr6a1-1 isoform expression. We perform identification of direct RNA interacting proteins (iDRIP) to identify proteins interacting directly with lnc-Nr6a1-1 isoform. We define a network of interacting proteins, including glycolytic enzymes, desmosome proteins and chaperone proteins and we demonstrated that lnc-Nr6a1-1 isoform directly binds and acts as a scaffold molecule for the assembly of ENO1, ALDOA, GAPDH, PKM glycolytic enzymes along with LDHA, supporting substrate canneling for efficient glycolysis. Our results unveil a role of lnc-Nr6a1 as a multifunctional lncRNA acting as a backbone for multiprotein complexes formation and as a primary microRNAs reservoir.

ORGANISM(S): Mus musculus

PROVIDER: GSE207916 | GEO | 2022/10/04

REPOSITORIES: GEO

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TGF-beta-upregulated Lnc-Nr6a1 acts as a reservoir of miR-181 and mediates assembly of a glycolytic complex [RNA-seq]

Project description:Long noncoding RNAs (lncRNAs) have emerged as key regulators in a wide range of biological processes. The involvement of lncRNAs in epithelial-to-mesenchymal transition (EMT) has been well stablished; however, the role as immediate-early regulators is still unclear. Here, we identified a mouse miRNA-host gene lncRNA (lnc-Nr6a1) early upregulated during EMT. We show that this lncRNA is processed giving rise to abundant polyadenylated isoforms, lnc-Nr6a1 and lnc-Nr6a1-2, and a longer non-polyadenylated microprocessor-driven lnc-pri-miRNAS containing clustered pre-miRNA-181a2 and pre-miRNA-181b2 hairpins. Ectopic expression of lnc-Nr6a1-1/2 isoforms enhance cell migration and invasive capacity of the cells, whereas the expression of isoforms and miR-181a2/b2 confers anoikis resistance. Lnc-Nr6a1 gene deletion results in cells with lower adhesion capacity and reduced glycolytic metabolism which are restored by lnc-Nr6a1-1 isoform expression. We perform identification of direct RNA interacting proteins (iDRIP) to identify proteins interacting directly with lnc-Nr6a1-1 isoform. We define a network of interacting proteins, including glycolytic enzymes, desmosome proteins and chaperone proteins and we demonstrated that lnc-Nr6a1-1 isoform directly binds and acts as a scaffold molecule for the assembly of ENO1, ALDOA, GAPDH, PKM glycolytic enzymes along with LDHA, supporting substrate canneling for efficient glycolysis. Our results unveil a role of lnc-Nr6a1 as a multifunctional lncRNA acting as a backbone for multiprotein complexes formation and as a primary microRNAs reservoir.

2022-10-04 | GSE207915 | GEO

Oncogenic HPV E7 promotes the expression of a long noncoding RNA lnc-FANCI-2 via YY1 and miR-29a

Project description:Long noncoding RNAs (lncRNA) play diverse roles in biological processes, but their expression profiles and functions in cervical carcinogenesis remains unknown. By RNA-seq analyses of 18 clinical samples and validated by RT-qPCR analyses of 72 clinical samples, we provide the first evidence in this report that 194 lncRNAs are differentially regulated by high-risk HPV infection along with cervical lesion progression. One such lncRNA, lnc-FANCI-2, induced by high-risk HPV infection was carefully analyzed because it is expressed from the same chr 15q26.1 region of FANCI gene encoding an important DNA repair factor. We found a mutual regulation of lnc-FANCI-2 and FANCI in cervical cancer cells and high-risk E6 and mainly E7 for this upregulation independent of p53 and pRb/E2F1. In HPV16-positive CaSki cells, lnc-FANCI-2, primarily in the cytoplasm in ~10 copies per cell, is transcribed from two alternative promoters and polyadenylated at two alternative poly(A) sites. Alternative RNA splicing of lnc-FANCI-2 transcripts leads to produce 14 detectable RNA isoforms. YY1 interacts with viral E7 and transactivates the transcription by binding to two YY1-binding motifs in the lnc-FANCI-2 promoter. Knockdown of either YY1 or E7 expression led to significant reduction of lnc-FANCI-2 expression. The 3’ untranslational region of YY-1 RNA contains a consensus seed match to miR-29a and is sensitive to miR-29a-mediated inhibition of YY1 expression. High-risk HPV infections were found to induce YY1 expression in HPV18-infected HFKs by reduction of host miR-29a expression. Together, our data have provided novel insights into mechanisms of how high-risk HPVs contribute to cervical carcinogenesis.

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miRNA-independent function of long noncoding pri-miRNA loci

Project description:Among the large, diverse set of mammalian long noncoding RNAs (lncRNAs), long noncoding primary microRNAs (lnc-pri-miRNAs) are those that host miRNAs. Whether lnc-pri-miRNA loci have important biological function independent of their cognate miRNAs is poorly understood. From a genome-scale lncRNA screen, lnc-pri-miRNA loci were enriched for function in cell proliferation, and in glioblastoma (i.e., GBM) cells with DGCR8 or DROSHA knockdown, lnc-pri-miRNA screen hits still regulated cell growth. To molecularly dissect the function of a lnc-pri-miRNA locus, we studied LOC646329 (also known as MIR29HG), which hosts the miR-29a/b1 cluster. In GBM cells, LOC646329 knockdown reduced miR-29a/b1 levels, and these cells exhibited decreased growth. However, genetic deletion of the miR-29a/b1 cluster (LOC646329-miR29Δ) did not decrease cell growth, while knockdown of LOC646329-miR29Δ transcripts reduced cell proliferation. The miR-29a/b1-independent activity of LOC646329 corresponded to enhancer-like activation of a neighboring oncogene (MKLN1), regulating cell propagation. The LOC646329 locus interacts with the MKLN1 promoter, and antisense oligonucleotide knockdown of the lncRNA disrupts these interactions and reduces the enhancer-like activity. More broadly, analysis of genome-wide data from multiple human cell types showed that lnc-pri-miRNA loci are significantly enriched for DNA looping interactions with gene promoters as well as genomic and epigenetic characteristics of transcriptional enhancers. Functional studies of additional lnc-pri-miRNA loci demonstrated cognate miRNA-independent enhancer-like activity. Together, these data demonstrate that lnc-pri-miRNA loci can regulate cell biology via both miRNA-dependent and miRNA-independent mechanisms.

2021-03-12 | GSE137048 | GEO

Microprocessor mediates transcription termination in long noncoding microRNA genes

Project description:MicroRNA (miRNA) play a major role in the post-transcriptional regulation of gene expression. In mammals most miRNA derive from the introns of protein coding genes where they exist as hairpin structures in the primary gene transcript, synthesized by RNA polymerase II (Pol II). These are cleaved co-transcriptionally by the Microprocessor complex, comprising DGCR8 and the RNase III endonuclease Drosha, to release the precursor (pre-)miRNA hairpin, so generating both miRNA and spliced messenger RNA1-4. However, a substantial minority of miRNA originate from Pol II-synthesized long non coding (lnc) RNA where transcript processing is largely uncharacterized5. Here, we show that most lnc-pri-miRNA do not use the canonical cleavage and polyadenylation (CPA) transcription termination pathway6, but instead use Microprocessor cleavage both to release pre-miRNA and terminate transcription. We present a detailed characterization of one such lnc-pri-miRNA that generates the highly expressed liver-specific miR-1227. Genome-wide analysis then reveals that Microprocessor-mediated transcription termination is commonly used by lnc-pri-miRNA but not by protein coding miRNA genes. This identifies a fundamental difference between lncRNA and pre-mRNA processing. Remarkably, inactivation of the Microprocessor can lead to extensive transcriptional readthrough of lnc-pri-miRNA, resulting in inhibition of downstream genes by transcriptional interference. Consequently we define a novel RNase III-mediated, polyadenylation-independent mechanism of Pol II transcription termination in mammalian cells. Chromatin associated RNA-seq from sicntrl,siDrosha,siDGCR8 treated Hela cells. Same for sicntrl and siDGCR8 from Huh7 cells. Nuclear polyA + and polyA- RNA-seq from sicntrl and siDGCR8 in HeLa cells. Chromatin associated RNA-seq from siDicer treated Hela cells.

2015-03-02 | E-GEOD-58838 | biostudies-arrayexpress

lnc-EAPV binding proteins in C57BL/6J BMDMs

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2018-11-07 | PXD011577 | Pride

Caenorhabditis japonica high resolution developmental transcriptomic time-course

Project description:Transcriptomic studies typically examine expression at the gene level, although it has been long recognized that the same genetic locus may produce isoforms distinct in their splicing and site of polyadenylation. Here we examine alternatively polyadenylated (APA) transcripts throughout embryogenesis and discover distinct strategies for gene regulation. We introduce APA-Seq, an RNA-Seq method to study APA at a global level, and apply it to study individual C. elegans embryos throughout early development. Surprisingly, we find that genes, whose overall expression is constitutive throughout development, generally show highly dynamic expression for individual isoforms. Such genes tend to participate in cellular as opposed to developmental processes, and this trend was also evident in the closely related C. japonica nematode, providing evidence that the manner by which cellular processes are regulated during embryogenesis is evolutionarily conserved. Finally, we report that genes with dynamic isoform usage have significantly more miRNA binding sites relative to constitutively-expressed isoforms, suggesting strong miRNA regulation in the control of isoform expression. Our findings support a model distinguishing two modes of gene regulatory underlying embryonic development each with unique functions and mechanisms.

2018-07-31 | GSE102398 | GEO

LncRNA-42060 Regulates Tamoxifen Sensitivity and Tumor Development via Regulating the miR-204-5p/SOX4 Axis in Canine Mammary Gland Tumor Cells

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2021-07-14 | GSE164721 | GEO

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2016-06-01 | E-GEOD-75880 | biostudies-arrayexpress

Comprehensive Identification of Long Non-coding RNAs in Purified Cell Types from the Brain Reveals Functional LncRNA in OPC Fate Determination (RNA-Seq of differentiated NSC after lnc-OPC knockdown)

Project description:To quantitative analysis of transcriptome changes caused by lnc-OPC knockdown during OPC differentiation from NSC, lentivirus-based short hairpin RNAs were used to knockdown the lnc-OPC expression in a neural stem cell culture . Subsequently, puromycin-selected NSCs were differentiated to OPC in culture for three days.RNA-Seq was performed on the polyadenylated fraction of RNA isolated from cell samples. DEseq was used for differential gene expression analysis caused by lnc-OPC knockdown. GO functional term enrichment analysis of differential gene expression caused by lnc-OPC knockdown, revealed significant enrichment of âoligodendrocyte developmentâ, âoligodendrocyte differentiationâ, âglia cell developmentâ, and âaxon ensheathmentâ terms that are associated with oligodendrogenesis. mRNA profiles of differentiiated NSC samples after lnc-OPC knockdown by RNA-sequencing.

2015-11-04 | E-GEOD-74647 | biostudies-arrayexpress

The Drosophila CoREST interactome

Project description:Affinity purification of dCoREST-interacting proteins from Drosophila melanogaster S2 cell nuclear extracts. An antibody recognizing both dCoREST isoforms was used to affinity purify proteins interacting with endogenous dCoREST from S2 nuclear extract. In addition, nuclear extracts from S2 cell lines ectopically expressing the FLAG-tagged dCoREST-L isoform and the FLAG-tagged dCoREST-M isoform, respectively, were subjected to anti-FLAG affinity purification to purify isoform specific dCoREST-interacting proteins.

2019-11-11 | PXD014857 | Pride

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