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The regulatory impact of RNA-binding proteins on microRNA targeting.

ABSTRACT: Argonaute is the primary mediator of metazoan miRNA targeting (MT). Among the currently identified >1,500 human RNA-binding proteins (RBPs), there are only a handful of RBPs known to enhance MT and several others reported to suppress MT, leaving the global impact of RBPs on MT elusive. In this study, we have systematically analyzed transcriptome-wide binding sites for 150 human RBPs and evaluated the quantitative effect of individual RBPs on MT efficacy. In contrast to previous studies, we show that most RBPs significantly affect MT and that all of those MT-regulating RBPs function as MT enhancers rather than suppressors, by making the local secondary structure of the target site accessible to Argonaute. Our findings illuminate the unappreciated regulatory impact of human RBPs on MT, and as these RBPs may play key roles in the gene regulatory network governed by metazoan miRNAs, MT should be understood in the context of co-regulating RBPs.

SUBMITTER: Kim S

PROVIDER: S-EPMC8379221 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The regulatory impact of RNA-binding proteins on microRNA targeting

Project description:Argonaute is the primary mediator of metazoan miRNA targeting (MT). Among the currently identified >1,500 human RNA-binding proteins (RBPs), there are only a handful of RBPs known to enhance MT and several others reported to suppress MT, leaving the global impact of RBPs on MT elusive. In this study, we have systematically analyzed transcriptome-wide binding sites for 150 human RBPs and evaluated the quantitative effect of individual RBPs on MT efficacy. In contrast to previous studies, we show that most RBPs significantly affect MT and that all of those MT-regulating RBPs function as MT enhancers rather than suppressors, by making the local secondary structure of the target site accessible to Argonaute. Our findings illuminate the unappreciated regulatory impact of human RBPs on MT, and as these RBPs may play key roles in the gene regulatory network governed by metazoan miRNAs, MT should be understood in the context of co-regulating RBPs.

2021-07-09 | GSE115646 | GEO

The regulatory impact of RNA-binding proteins on microRNA targeting

Project description:The regulatory impact of RNA-binding proteins on microRNA targeting

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Systematic Discovery of RNA Binding Proteins that Regulate MicroRNA Levels.

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Project description:BackgroundThe myeloid translocation gene (MTG) proteins are non-DNA-binding transcriptional regulators capable of interacting with chromatin modifying proteins. As a consequence of leukemia-associated chromosomal translocations, two of the MTG proteins, MTG8 and MTG16, are fused to the DNA-binding domain of AML1, a transcriptional activator crucial for hematopoiesis. The AML1-MTG fusion proteins, as the wild type MTGs, display four conserved homology regions (NHR1-4) related to the Drosophila nervy protein. Structural protein analyses led us to test the hypothesis that specific MTG domains may mediate RNA binding.ResultsBy using an RNA-binding assay based on synthetic RNA homopolymers and a panel of MTG deletion mutants, here we show that all the MTG proteins can bind RNA. The RNA-binding properties can be traced to two regions: the Zinc finger domains in the NHR4, which mediate Zinc-dependent RNA binding, and a novel short basic region (SBR) upstream of the NHR2, which mediates Zinc-independent RNA binding. The two AML1-MTG fusion proteins, retaining both the Zinc fingers domains and the SBR, also display RNA-binding properties.ConclusionEvidence has been accumulating that RNA plays a role in transcriptional control. Both wild type MTGs and chimeric AML1-MTG proteins display in vitro RNA-binding properties, thus opening new perspectives on the possible involvement of an RNA component in MTG-mediated chromatin regulation.

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MicroRNA-24 targeting RNA-binding protein DND1 in tongue squamous cell carcinoma.

Project description:Deregulations of microRNA have been frequently observed in tongue squamous cell carcinoma (TSCC), but their roles in tumorigenesis are not entirely clear. Here, we reported the up-regulation of miR-24 in TSCC. MiR-24 up-regulation reduced the expression of RNA-binding protein dead end 1 (DND1). Knockdown of miR-24 led to enhanced expression of DND1. The direct targeting of miR-24 to the DND1 mRNA was predicted bioinformatically and confirmed by luciferase reporter gene assays. Furthermore, the miR-24-mediated change in DND1 expression suppressed the expression of cyclin-dependent kinase inhibitor 1B (CDKN1B), and also led to enhanced proliferation and reduced apoptosis in TSCC cells.

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Signatures of RNA binding proteins globally coupled to effective microRNA target sites.

Project description:MicroRNAs (miRNAs) and small interfering RNAs (siRNAs), bound to Argonaute proteins (RISC), destabilize mRNAs through base-pairing with the mRNA. However, the gene expression changes after perturbations of these small RNAs are only partially explained by predicted miRNA/siRNA targeting. Targeting may be modulated by other mRNA sequence elements such as binding sites for the hundreds of RNA binding proteins (RNA-BPs) expressed in any cell, and this aspect has not been systematically explored. Across a panel of published experiments, we systematically investigated to what extent sequence motifs in 3' untranslated regions (UTRs) correlate with expression changes following transfection of small RNAs. The most significantly overrepresented motifs in down-regulated mRNAs are two novel U-rich motifs (URMs), UUUUAAA and UUUGUUU, recently discovered as binding sites for the ELAVL4 (also known as HuD) RNA-BP. Surprisingly, the most significantly overrepresented motif in up-regulated mRNAs is the heptanucleotide AU-rich element (ARE), UAUUUAU, which is known to affect mRNA stability via at least 20 different RNA-BPs. We show that destabilization mediated by the transfected miRNA is generally attenuated by ARE motifs and augmented by URM motifs. These ARE and URM signatures were confirmed in different types of published experiments covering eight different cell lines. Finally, we show that both ARE and URM motifs couple to presumed endogenous miRNA binding sites in mRNAs bound by Argonaute proteins. This is the first systematic investigation of 3' UTR motifs that globally couple to regulation by miRNAs and may potentially antagonize or cooperate with miRNA/siRNA regulation. Our results suggest that binding sites of miRNAs and RNA-BPs should be considered in combination when interpreting and predicting miRNA regulation in vivo.

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CELF Family Proteins in Cancer: Highlights on the RNA-Binding Protein/Noncoding RNA Regulatory Axis.

Project description:Post-transcriptional modifications to coding and non-coding RNAs are unquestionably a pivotal way in which human mRNA and protein diversity can influence the different phases of a transcript's life cycle. CELF (CUGBP Elav-like family) proteins are RBPs (RNA-binding proteins) with pleiotropic capabilities in RNA processing. Their responsibilities extend from alternative splicing and transcript editing in the nucleus to mRNA stability, and translation into the cytoplasm. In this way, CELF family members have been connected to global alterations in cancer proliferation and invasion, leading to their identification as potential tumor suppressors or even oncogenes. Notably, genetic variants, alternative splicing, phosphorylation, acetylation, subcellular distribution, competition with other RBPs, and ultimately lncRNAs, miRNAs, and circRNAs all impact CELF regulation. Discoveries have emerged about the control of CELF functions, particularly via noncoding RNAs, and CELF proteins have been identified as competing, antagonizing, and regulating agents of noncoding RNA biogenesis. On the other hand, CELFs are an intriguing example through which to broaden our understanding of the RBP/noncoding RNA regulatory axis. Balancing these complex pathways in cancer is undeniably pivotal and deserves further research. This review outlines some mechanisms of CELF protein regulation and their functional consequences in cancer physiology.

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Project description:In eukaryotic organisms, gene expression requires an additional level of coordination that links transcriptional and posttranslational processes. Messenger RNAs have traditionally been viewed as passive molecules in the pathway from transcription to translation. However, it is now clear that RNA-binding proteins (RBPs) play an important role in cellular homeostasis by controlling gene expression at the posttranscriptional level. Here, we show that RBPs, as a class of proteins, show distinct gene expression dynamics compared to other protein coding genes in the eukaryote Sacchoromyces cerevisiae. We find that RBPs generally exhibit high protein stability, translational efficiency, and protein abundance but their encoding transcripts tend to have a low half-life. We show that RBPs are also most often posttranslationally modified, indicating their potential for regulation at the protein level to control diverse cellular processes. Further analysis of the RBP-RNA interaction network showed that the number of distinct targets bound by an RBP (connectivity) is strongly correlated with its protein stability, translational efficiency, and abundance. We also note that RBPs show less noise in their expression in a population of cells, with highly connected RBPs showing significantly lower noise. Our results indicate that highly connected RBPs are likely to be tightly regulated at the protein level as significant changes in their expression may bring about large-scale changes in global expression levels by affecting their targets. These observations might explain the molecular basis behind the cause of a number of disorders associated with misexpression or mutation in RBPs. Future studies uncovering the posttranscriptional networks in higher eukaryotes can help our understanding of the link between different levels of regulation and their role in pathological conditions.

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