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      The emerging roles of long noncoding RNAs in lymphatic vascular development and disease

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          Abstract

          Recent advances in RNA sequencing technologies helped uncover what was once uncharted territory in the human genome—the complex and versatile world of long noncoding RNAs (lncRNAs). Previously thought of as merely transcriptional “noise”, lncRNAs have now emerged as essential regulators of gene expression networks controlling development, homeostasis and disease progression. The regulatory functions of lncRNAs are broad and diverse, and the underlying molecular mechanisms are highly variable, acting at the transcriptional, post-transcriptional, translational, and post-translational levels. In recent years, evidence has accumulated to support the important role of lncRNAs in the development and functioning of the lymphatic vasculature and associated pathological processes such as tumor-induced lymphangiogenesis and cancer metastasis. In this review, we summarize the current knowledge on the role of lncRNAs in regulating the key genes and pathways involved in lymphatic vascular development and disease. Furthermore, we discuss the potential of lncRNAs as novel therapeutic targets and outline possible strategies for the development of lncRNA-based therapeutics to treat diseases of the lymphatic system.

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          Most cited references308

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          Natural RNA circles function as efficient microRNA sponges.

          MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression that act by direct base pairing to target sites within untranslated regions of messenger RNAs. Recently, miRNA activity has been shown to be affected by the presence of miRNA sponge transcripts, the so-called competing endogenous RNA in humans and target mimicry in plants. We previously identified a highly expressed circular RNA (circRNA) in human and mouse brain. Here we show that this circRNA acts as a miR-7 sponge; we term this circular transcript ciRS-7 (circular RNA sponge for miR-7). ciRS-7 contains more than 70 selectively conserved miRNA target sites, and it is highly and widely associated with Argonaute (AGO) proteins in a miR-7-dependent manner. Although the circRNA is completely resistant to miRNA-mediated target destabilization, it strongly suppresses miR-7 activity, resulting in increased levels of miR-7 targets. In the mouse brain, we observe overlapping co-expression of ciRS-7 and miR-7, particularly in neocortical and hippocampal neurons, suggesting a high degree of endogenous interaction. We further show that the testis-specific circRNA, sex-determining region Y (Sry), serves as a miR-138 sponge, suggesting that miRNA sponge effects achieved by circRNA formation are a general phenomenon. This study serves as the first, to our knowledge, functional analysis of a naturally expressed circRNA.
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            The biogenesis, biology and characterization of circular RNAs

            Circular RNAs (circRNAs) are covalently closed, endogenous biomolecules in eukaryotes with tissue-specific and cell-specific expression patterns, whose biogenesis is regulated by specific cis-acting elements and trans-acting factors. Some circRNAs are abundant and evolutionarily conserved, and many circRNAs exert important biological functions by acting as microRNA or protein inhibitors ('sponges'), by regulating protein function or by being translated themselves. Furthermore, circRNAs have been implicated in diseases such as diabetes mellitus, neurological disorders, cardiovascular diseases and cancer. Although the circular nature of these transcripts makes their detection, quantification and functional characterization challenging, recent advances in high-throughput RNA sequencing and circRNA-specific computational tools have driven the development of state-of-the-art approaches for their identification, and novel approaches to functional characterization are emerging.
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              Gene regulation by long non-coding RNAs and its biological functions

              Evidence accumulated over the past decade shows that long non-coding RNAs (lncRNAs) are widely expressed and have key roles in gene regulation. Recent studies have begun to unravel how the biogenesis of lncRNAs is distinct from that of mRNAs and is linked with their specific subcellular localizations and functions. Depending on their localization and their specific interactions with DNA, RNA and proteins, lncRNAs can modulate chromatin function, regulate the assembly and function of membraneless nuclear bodies, alter the stability and translation of cytoplasmic mRNAs and interfere with signalling pathways. Many of these functions ultimately affect gene expression in diverse biological and physiopathological contexts, such as in neuronal disorders, immune responses and cancer. Tissue-specific and condition-specific expression patterns suggest that lncRNAs are potential biomarkers and provide a rationale to target them clinically. In this Review, we discuss the mechanisms of lncRNA biogenesis, localization and functions in transcriptional, post-transcriptional and other modes of gene regulation, and their potential therapeutic applications.
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                Author and article information

                Contributors
                konstantin.i.ivanov@gmail.com , konstantin.ivanov@helsinki.fi
                Journal
                Cell Mol Life Sci
                Cell Mol Life Sci
                Cellular and Molecular Life Sciences
                Springer International Publishing (Cham )
                1420-682X
                1420-9071
                6 July 2023
                6 July 2023
                2023
                : 80
                : 8
                : 197
                Affiliations
                [1 ]GRID grid.510477.0, Research Center for Translational Medicine, , Sirius University of Science and Technology, ; Sochi, Russian Federation
                [2 ]GRID grid.7737.4, ISNI 0000 0004 0410 2071, Department of Microbiology, , University of Helsinki, ; Helsinki, Finland
                [3 ]GRID grid.448878.f, ISNI 0000 0001 2288 8774, Department of Biochemistry, , Sechenov First Moscow State Medical University, ; Moscow, Russian Federation
                [4 ]GRID grid.410682.9, ISNI 0000 0004 0578 2005, HSE University, ; Moscow, Russian Federation
                [5 ]GRID grid.14476.30, ISNI 0000 0001 2342 9668, Faculty of Bioengineering and Bioinformatics, , Lomonosov Moscow State University, ; Moscow, Russian Federation
                [6 ]GRID grid.14476.30, ISNI 0000 0001 2342 9668, Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, ; Moscow, Russian Federation
                [7 ]GRID grid.5475.3, ISNI 0000 0004 0407 4824, Faculty of Health and Medical Sciences, , University of Surrey, ; Guildford, UK
                Author information
                http://orcid.org/0000-0001-9198-5674
                http://orcid.org/0000-0002-1195-9116
                http://orcid.org/0000-0002-3046-4565
                Article
                4842
                10.1007/s00018-023-04842-4
                10322780
                37407839
                c3dec6ab-1970-40b9-8953-4c1260261274
                © The Author(s) 2023

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 8 November 2022
                : 6 June 2023
                : 19 June 2023
                Funding
                Funded by: Russian Science Foundation
                Award ID: 21-75-30020
                Award Recipient :
                Funded by: University of Helsinki including Helsinki University Central Hospital
                Categories
                Review
                Custom metadata
                © Springer Nature Switzerland AG 2023

                Molecular biology
                lncrna,lymphatics,regulation of gene expression,lymph node metastasis (lnm),lymphatic vessels,lymphatic endothelial cells (lecs),gene regulation,long non-coding rna

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