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      LNCcation: lncRNA localization and function

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          Abstract

          Bridges et al. discuss current knowledge, lingering questions, and emerging themes surrounding lncRNA subcellular localization and its impact on cellular functions.

          Abstract

          Subcellular localization of RNAs has gained attention in recent years as a prevalent phenomenon that influences numerous cellular processes. This is also evident for the large and relatively novel class of long noncoding RNAs (lncRNAs). Because lncRNAs are defined as RNA transcripts >200 nucleotides that do not encode protein, they are themselves the functional units, making their subcellular localization critical to their function. The discovery of tens of thousands of lncRNAs and the cumulative evidence involving them in almost every cellular activity render assessment of their subcellular localization essential to fully understanding their biology. In this review, we summarize current knowledge of lncRNA subcellular localization, factors controlling their localization, emerging themes, including the role of lncRNA isoforms and the involvement of lncRNAs in phase separation bodies, and the implications of lncRNA localization on their function and on cellular behavior. We also discuss gaps in the current knowledge as well as opportunities that these provide for novel avenues of investigation.

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          Most cited references224

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          Biomolecular condensates: organizers of cellular biochemistry

          In addition to membrane-bound organelles, eukaryotic cells feature various membraneless compartments, including the centrosome, the nucleolus and various granules. Many of these compartments form through liquid–liquid phase separation, and the principles, mechanisms and regulation of their assembly as well as their cellular functions are now beginning to emerge.
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            Long noncoding RNA as modular scaffold of histone modification complexes.

            Long intergenic noncoding RNAs (lincRNAs) regulate chromatin states and epigenetic inheritance. Here, we show that the lincRNA HOTAIR serves as a scaffold for at least two distinct histone modification complexes. A 5' domain of HOTAIR binds polycomb repressive complex 2 (PRC2), whereas a 3' domain of HOTAIR binds the LSD1/CoREST/REST complex. The ability to tether two distinct complexes enables RNA-mediated assembly of PRC2 and LSD1 and coordinates targeting of PRC2 and LSD1 to chromatin for coupled histone H3 lysine 27 methylation and lysine 4 demethylation. Our results suggest that lincRNAs may serve as scaffolds by providing binding surfaces to assemble select histone modification enzymes, thereby specifying the pattern of histone modifications on target genes.
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              Circular RNAs are abundant, conserved, and associated with ALU repeats.

              Circular RNAs composed of exonic sequence have been described in a small number of genes. Thought to result from splicing errors, circular RNA species possess no known function. To delineate the universe of endogenous circular RNAs, we performed high-throughput sequencing (RNA-seq) of libraries prepared from ribosome-depleted RNA with or without digestion with the RNA exonuclease, RNase R. We identified >25,000 distinct RNA species in human fibroblasts that contained non-colinear exons (a "backsplice") and were reproducibly enriched by exonuclease degradation of linear RNA. These RNAs were validated as circular RNA (ecircRNA), rather than linear RNA, and were more stable than associated linear mRNAs in vivo. In some cases, the abundance of circular molecules exceeded that of associated linear mRNA by >10-fold. By conservative estimate, we identified ecircRNAs from 14.4% of actively transcribed genes in human fibroblasts. Application of this method to murine testis RNA identified 69 ecircRNAs in precisely orthologous locations to human circular RNAs. Of note, paralogous kinases HIPK2 and HIPK3 produce abundant ecircRNA from their second exon in both humans and mice. Though HIPK3 circular RNAs contain an AUG translation start, it and other ecircRNAs were not bound to ribosomes. Circular RNAs could be degraded by siRNAs and, therefore, may act as competing endogenous RNAs. Bioinformatic analysis revealed shared features of circularized exons, including long bordering introns that contained complementary ALU repeats. These data show that ecircRNAs are abundant, stable, conserved and nonrandom products of RNA splicing that could be involved in control of gene expression.
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                Author and article information

                Journal
                J Cell Biol
                J Cell Biol
                jcb
                The Journal of Cell Biology
                Rockefeller University Press
                0021-9525
                1540-8140
                01 February 2021
                19 January 2021
                : 220
                : 2
                : e202009045
                Affiliations
                [1]Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC
                Author notes
                Correspondence to Antonis Kourtidis: kourtidi@ 123456musc.edu
                Author information
                https://orcid.org/0000-0003-1101-0848
                https://orcid.org/0000-0002-6090-957X
                https://orcid.org/0000-0002-8128-6391
                Article
                jcb.202009045
                10.1083/jcb.202009045
                7816648
                33464299
                a18e2268-3882-4e3f-a1da-3ff75e6374b7
                © 2021 Bridges et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

                History
                : 14 September 2020
                : 20 December 2020
                : 23 December 2020
                Page count
                Pages: 17
                Funding
                Funded by: National Institutes of Health, DOI http://doi.org/10.13039/100000002;
                Award ID: P20 GM130457-01A1
                Award ID: R21 CA246233-01A1
                Award ID: P30 DK123704-01
                Funded by: National Institutes of Health, DOI http://doi.org/10.13039/100000002;
                Award ID: TL1 TR001451
                Award ID: UL1 TR001450
                Categories
                Review
                RNA biology

                Cell biology
                Cell biology

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