Nuclear microRNA-466c regulates Vegfa expression in response to hypoxia

Laitinen, Pia; Väänänen, Mari-Anna; Kolari, Ida-Liisa; Mäkinen, Petri; Kaikkonen, Minna U.; Weinberg, Marc S.; Morris, Kevin V.; Korhonen, Paula; Malm, Tarja; Ylä‐Herttuala, Seppo; Roberts, Thomas C.; Turunen, Mikko P.; Turunen, Tiia A.

doi:10.1371/journal.pone.0265948

Cited by 10 publications

(3 citation statements)

References 54 publications

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“…Previous studies have demonstrated miRNA activity involved in the regulation of gene expression within the nucleus (Laitinen et al 2022;Leucci et al 2013), the work presented here suggests that this may be more extensive than previously considered. There are a number of exciting possibilities for the link between cytoplasmic IR and miRNA activity -introns might sequester miRNA in the cytoplasm, which consequently impacts the nuclear function of these miRNA or they could act as transport shuttles that physically localise miRNA between the two compartments.…”

Section: Discussionsupporting

confidence: 50%

Physiological intron retaining transcripts in the cytoplasm abound during human motor neurogenesis

et al. 2022

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Intron retention (IR) is now recognized as a dominant splicing event during motor neuron (MN) development, however the role and regulation of intron-retaining transcripts (IRTs) localized to the cytoplasm remain particularly understudied. Here we show that IR is a physiological process that is spatiotemporally regulated during MN lineage restriction and that IRTs in the cytoplasm are detected in as many as 13% (n=2297) of the genes expressed during this process. We identify a major class of cytoplasmic IRTs, which are not associated with reduced expression of their own genes, but instead show a high capacity for RNA-binding protein and miRNA occupancy. Finally, we show that ALS-causing VCP mutations lead to a selective increase in cytoplasmic abundance of this particular class of IRTs, which in turn temporally coincides with an increase in the nuclear expression level of predicted miRNA target genes. Altogether, our study identifies a previously unrecognized class of cytoplasmic intronic sequences with potential regulatory function beyond gene expression.

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Section: Discussionsupporting

confidence: 50%

Physiological intron retaining transcripts in the cytoplasm abound during human motor neurogenesis

et al. 2022

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“…In the mouse endothelial cell line C166, Laitinen et al discovered in 2022 that the nuclear microRNA miR-466c regulates the production of vascular endothelial growth factor a (VEGFA) when the environment is hypoxic (30). Additionally, the miR-466c deletion in the CRISPR-Cas9 genome greatly hinders the hypoxia-induced increase in VEGFA content.…”

Section: Potential Signaling Pathways Associated With the Nuclear Mir...mentioning

confidence: 99%

Recent advances in the functional explorations of nuclear microRNAs

Yin

Zhang

et al. 2023

Front. Immunol.

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Approximately 22 nucleotide-long non-coding small RNAs (ncRNAs) play crucial roles in physiological and pathological activities, including microRNAs (miRNAs). Long ncRNAs often stay in the cytoplasm, modulating post-transcriptional gene expression. Briefly, miRNA binds with the target mRNA and builds a miRNA-induced silencing complex to silence the transcripts or prevent their translation. Interestingly, data from recent animal and plant studies suggested that mature miRNAs are present in the nucleus, where they regulate transcriptionally whether genes are activated or silenced. This significantly broadens the functional range of miRNAs. Here, we reviewed and summarized studies on the functions of nuclear miRNAs to better understand the modulatory networks associated with nuclear miRNAs.

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“…Yet these targets still may not reveal the whole story of how the miRNAs could impact infection. Recently, there has been increasing evidence that miRNA functional mechanisms are not limited to 3'UTR targeting and it has been shown that AGO:miRNAs can also regulate transcription through interaction with promoter-associated lncRNAs, leading to either activation or inhibition of gene expression in the nucleus (73)(74)(75)(76)(77). We therefore wished to take advantage of our chimeric data and HC filters to determine whether we find evidence for targets mapping to regulatory regions.…”

Section: Pseudogenes and Lncrnas Are Hc Mirna Targets And Nuclear Loc...mentioning

confidence: 99%

RNA-RNA interactions between Respiratory syncytial virus and miR-26 and miR-27 are associated with regulation of cell cycle and antiviral immunity

Ressel

Kumar

Bermúdez-Barrientos

et al. 2023

Preprint

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Specific viruses can sequester or inhibit miRNAs through direct RNA-RNA interactions to enable their life cycle, but we still lack comprehensive understanding of the existence and functions of such interactions in respiratory virus infections. Here we optimise the CLEAR-CLIP protocol in A549 cells and show that Respiratory syncytial virus (RSV) directly binds miR-26, miR-27, and let-7. We show a significant global up-regulation of miR-26 targets upon RSV infection as well as up-regulation of miR-27 targets involved in cell cycle regulation and immune signalling. Through genome analysis of miRNA-target reads we further show that pseudogenes which overlap transcriptional regulatory regions are functional miRNA targets. We identify and validate an interaction between miR-27 and a pseudogene-derived lncRNA that overlaps an enhancer and show that this interaction regulates expression of Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). This work demonstrates that RSV directly interacts with host miRNAs to de-regulate host gene expression and provides biochemical support for the ability of miRNAs to directly regulate gene transcription linked to immune signalling.

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Nuclear microRNA-466c regulates Vegfa expression in response to hypoxia

Cited by 10 publications

References 54 publications

Physiological intron retaining transcripts in the cytoplasm abound during human motor neurogenesis

Physiological intron retaining transcripts in the cytoplasm abound during human motor neurogenesis

Recent advances in the functional explorations of nuclear microRNAs

RNA-RNA interactions between Respiratory syncytial virus and miR-26 and miR-27 are associated with regulation of cell cycle and antiviral immunity

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