The regulatory impact of RNA-binding proteins on microRNA targeting

Kim, Suk-Jun; Kim, Soyoung; Chang, Hee Ryung; Kim, Doyeon; Park, June-Hee; Son, Narae; Park, Joori; Yoon, Minhyuk; Chae, Gwangung; Kim, Young‐Kook; Kim, V. Narry; Kim, Yoon Ki; Nam, Jin‐Wu; Shin, Chanseok; Baek, Daehyun

doi:10.1038/s41467-021-25078-5

Cited by 71 publications

(49 citation statements)

References 62 publications

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“…For two of the four modes in the model, methylation facilitated target binding by miRNAs. In another recent study with a focus on RBPs and miRNA targeting, most RBPs were found to enhance miRNA targeting by increasing target site accessibility ( Kim et al , 2021 ). For miRNA targeting, the importance of target structure and binding site accessibility was established over 14 years ago ( Long et al , 2007 ).…”

Section: Discussionmentioning

confidence: 99%

N 6-methyladenosine enhances post-transcriptional gene regulation by microRNAs

Kanoria

Rennie

Carmack

et al. 2022

Bioinformatics Advances

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Motivation N 6-methyladenosine (m6A) is the most prevalent modification in eukaryotic messenger RNAs. MicroRNAs are abundant post-transcriptional regulators of gene expression. Correlation between m6A and microRNA targeting sites has been reported to suggest possible involvement of m6A in microRNA-mediated gene regulation. However, it is unknown what the regulatory effects might be. In this study, we performed comprehensive analyses of high throughput data on m6A and microRNA target binding and regulation. Results We found that the level of miRNA-mediated target suppression is significantly enhanced when m6A is present on target mRNAs. The evolutionary conservation for miRNA binding sites with m6A modification is significantly higher than that for miRNA binding sites without modification. These findings suggest functional significance of m6A modification in posttranscriptional gene regulation by microRNAs. We also found that methylated targets have more stable structure than non-methylated targets, as indicated by significantly higher GC content. Furthermore, miRNA binding sites that can be potentially methylated are significantly less accessible without methylation than those that do not possess potential methylation sites. Since either RNA binding proteins or m6A modification by itself can destabilize RNA structure, we propose a model in which m6A alters local target secondary structure to increase accessibility for efficient binding by Argonaute proteins, leading to enhanced miRNA-mediated regulation.

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Section: Discussionmentioning

confidence: 99%

N 6-methyladenosine enhances post-transcriptional gene regulation by microRNAs

Kanoria

Rennie

Carmack

et al. 2022

Bioinformatics Advances

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“…It appears that some effects of these miRNAs are cell type specific. miRNA-mRNA binding in cells is influenced by other regulatory factors (RNA binding Proteins, miRNA sponges) causing such differences in miRNA-mRNA interaction in various cell lines [ 47 – 49 ]. The effect of miR-24 on STING signaling is independent of cGAS, as experiments with STING agonist cGAMP also depicted the regulatory role of miR-24 on STING signaling ( S1B Fig ).…”

Section: Discussionmentioning

confidence: 99%

Herpes simplex virus 1 evades cellular antiviral response by inducing microRNA-24, which attenuates STING synthesis

et al. 2021

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STING is a nodal point for cellular innate immune response to microbial infections, autoimmunity and cancer; it triggers the synthesis of the antiviral proteins, type I interferons. Many DNA viruses, including Herpes Simplex Virus 1 (HSV1), trigger STING signaling causing inhibition of virus replication. Here, we report that HSV1 evades this antiviral immune response by inducing a cellular microRNA, miR-24, which binds to the 3’ untranslated region of STING mRNA and inhibits its translation. Expression of the gene encoding miR-24 is induced by the transcription factor AP1 and activated by MAP kinases in HSV1-infected cells. Introduction of exogenous miR-24 or prior activation of MAPKs, causes further enhancement of HSV1 replication in STING-expressing cells. Conversely, transfection of antimiR-24 inhibits virus replication in those cells. HSV1 infection of mice causes neuropathy and death; using two routes of infection, we demonstrated that intracranial injection of antimiR-24 alleviates both morbidity and mortality of the infected mice. Our studies reveal a new immune evasion strategy adopted by HSV1 through the regulation of STING and demonstrates that it can be exploited to enhance STING’s antiviral action.

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“…In addition, intergenic regions that are involved in the process of non-coding RNA biogenesis are also enriched for CELF proteins [7,8,12]. RBPs have recently been found to improve miRNA targeting (MT) by opening mRNA secondary structures [2]. Notably, the "UU-UGUUU" motifs, which are similar to CELF binding sites, are enriched adjacent to miRNA binding sites, and their presence tends to potentiate miRNA activity [150].…”

Section: Noncoding Rna Regulation By Celfmentioning

confidence: 99%

“…According to a new discovery, the RNA structure becomes more open as the number of bound RBPs rises. When the RNA becomes less organized, miRNAbound AGO may easily reach the MT sites by replacing the RBPs that were previously bound, resulting in productive MT [2]. However, to address the complex relation between RBPs and noncoding RNA production more conclusively, future efforts should be made to generate and analyze large-scale transcriptomic and proteomics datasets.…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

“…The widespread functions of RBPs range from splicing, localization, modification, stability, and translation of coding and noncoding RNAs [1]. In human cells, it is expected that approximately 1500 RBPs associate with over 33 million interactions in 3 UTR binding sites [2]. RBPs' multifunctionality, their broad number of targets and subcellular location, as well as their tight interactions with other RBPs and noncoding RNAs, make them a challenging field to research, especially in cancer, where modifications in the expression, mutations, and copy number variations of RBPs can have a significant impact on their performance [3,4].…”

Section: Introductionmentioning

confidence: 99%

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

Aghdam

Jave‐Suárez

2021

IJMS

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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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The regulatory impact of RNA-binding proteins on microRNA targeting

Cited by 71 publications

References 62 publications

N 6-methyladenosine enhances post-transcriptional gene regulation by microRNAs

N 6-methyladenosine enhances post-transcriptional gene regulation by microRNAs

Herpes simplex virus 1 evades cellular antiviral response by inducing microRNA-24, which attenuates STING synthesis

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

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