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      In vivo functional analysis of non-conserved human lncRNAs associated with cardiometabolic traits

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          Abstract

          Unlike protein-coding genes, the majority of human long non-coding RNAs (lncRNAs) are considered non-conserved. Although lncRNAs have been shown to function in diverse pathophysiological processes in mice, it remains largely unknown whether human lncRNAs have such in vivo functions. Here, we describe an integrated pipeline to define the in vivo function of non-conserved human lncRNAs. We first identify lncRNAs with high function potential using multiple indicators derived from human genetic data related to cardiometabolic traits, then define lncRNA’s function and specific target genes by integrating its correlated biological pathways in humans and co-regulated genes in a humanized mouse model. Finally, we demonstrate that the in vivo function of human-specific lncRNAs can be successfully examined in the humanized mouse model, and experimentally validate the predicted function of an obesity-associated lncRNA, LINC01018, in regulating the expression of genes in fatty acid oxidation in humanized livers through its interaction with RNA-binding protein HuR.

          Abstract

          Majority of human long non-coding RNAs (lncRNAs) are not conserved in mouse. Here the authors identify metabolic trait-associated lncRNA genes and show a functional role of a non-conserved human lncRNA, LINC01018, in lipid metabolism using a humanized mouse model.

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          Most cited references16

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          The evolution of lncRNA repertoires and expression patterns in tetrapods.

          Only a very small fraction of long noncoding RNAs (lncRNAs) are well characterized. The evolutionary history of lncRNAs can provide insights into their functionality, but the absence of lncRNA annotations in non-model organisms has precluded comparative analyses. Here we present a large-scale evolutionary study of lncRNA repertoires and expression patterns, in 11 tetrapod species. We identify approximately 11,000 primate-specific lncRNAs and 2,500 highly conserved lncRNAs, including approximately 400 genes that are likely to have originated more than 300 million years ago. We find that lncRNAs, in particular ancient ones, are in general actively regulated and may function predominantly in embryonic development. Most lncRNAs evolve rapidly in terms of sequence and expression levels, but tissue specificities are often conserved. We compared expression patterns of homologous lncRNA and protein-coding families across tetrapods to reconstruct an evolutionarily conserved co-expression network. This network suggests potential functions for lncRNAs in fundamental processes such as spermatogenesis and synaptic transmission, but also in more specific mechanisms such as placenta development through microRNA production.
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            HuR and mRNA stability.

            An important mechanism of posttranscriptional gene regulation in mammalian cells is the rapid degradation of messenger RNAs (mRNAs) signaled by AU-rich elements (AREs) in their 3' untranslated regions. HuR, a ubiquitously expressed member of the Hu family of RNA-binding proteins related to Drosophila ELAV, selectively binds AREs and stabilizes ARE-containing mRNAs when overexpressed in cultured cells. This review discusses mRNA decay as a general form of gene regulation, decay signaled by AREs, and the role of HuR and its Hu-family relatives in antagonizing this mRNA degradation pathway. The influence of newly identified protein ligands to HuR on HuR function in both normal and stressed cells may explain how ARE-mediated mRNA decay is regulated in response to environmental change.
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              Evolutionary dynamics and tissue specificity of human long noncoding RNAs in six mammals

              Long intergenic noncoding RNAs (lincRNAs) play diverse regulatory roles in human development and disease, but little is known about their evolutionary history and constraint. Here, we characterize human lincRNA expression patterns in nine tissues across six mammalian species and multiple individuals. Of the 1898 human lincRNAs expressed in these tissues, we find orthologous transcripts for 80% in chimpanzee, 63% in rhesus, 39% in cow, 38% in mouse, and 35% in rat. Mammalian-expressed lincRNAs show remarkably strong conservation of tissue specificity, suggesting that it is selectively maintained. In contrast, abundant splice-site turnover suggests that exact splice sites are not critical. Relative to evolutionarily young lincRNAs, mammalian-expressed lincRNAs show higher primary sequence conservation in their promoters and exons, increased proximity to protein-coding genes enriched for tissue-specific functions, fewer repeat elements, and more frequent single-exon transcripts. Remarkably, we find that ∼20% of human lincRNAs are not expressed beyond chimpanzee and are undetectable even in rhesus. These hominid-specific lincRNAs are more tissue specific, enriched for testis, and faster evolving within the human lineage.
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                Author and article information

                Contributors
                haiming.cao@nih.gov
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                2 January 2020
                2 January 2020
                2020
                : 11
                : 45
                Affiliations
                [1 ]ISNI 0000 0001 2297 5165, GRID grid.94365.3d, Cardiovascular Branch, National Heart, Lung and Blood Institute, , National Institutes of Health, ; Bethesda, MD 20892 USA
                [2 ]ISNI 0000 0001 2297 5165, GRID grid.94365.3d, Bioinformatics and Computational Biology Core, National Heart Lung and Blood Institute, , National Institutes of Health, ; Bethesda, MD 20892 USA
                [3 ]ISNI 0000 0004 0376 978X, GRID grid.452212.2, Laboratory Animal Research Department, Biomedical Research Laboratory, , Central Institute for Experimental Animals, ; 3-25-12 Tonomachi, Kawasaki-ku, Kawasaki 210-0821 Japan
                [4 ]Technical Service Department, CLEA Japan, Inc, 4839-23 Kitayama, Fujinomiya, Shizuoka 418-0122 Japan
                [5 ]ISNI 0000 0001 2355 7002, GRID grid.4367.6, Present Address: Division of Biology and Biomedical Sciences, , Washington University School of Medicine, ; St. Louis, Missouri USA
                Author information
                http://orcid.org/0000-0002-7333-9561
                http://orcid.org/0000-0002-4549-9517
                http://orcid.org/0000-0002-4210-6458
                http://orcid.org/0000-0002-3706-2454
                Article
                13688
                10.1038/s41467-019-13688-z
                6940387
                31896749
                e6524921-c031-4df0-bc08-e3a2cf334667
                © This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2020

                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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 4 February 2019
                : 14 November 2019
                Funding
                Funded by: FundRef https://doi.org/10.13039/100000002, U.S. Department of Health & Human Services | National Institutes of Health (NIH);
                Award ID: HL006103
                Award ID: HL006159
                Award Recipient :
                Funded by: U.S. Department of Health & Human Services | National Institutes of Health (NIH)
                Categories
                Article
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                © The Author(s) 2020

                Uncategorized
                genetics,molecular biology,long non-coding rnas,diseases
                Uncategorized
                genetics, molecular biology, long non-coding rnas, diseases

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