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      Long non-coding RNAs are involved in alternative splicing and promote cancer progression

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          Abstract

          Alternative splicing (AS) is a key process in which precursor RNAs produce different mature RNAs, and the disorder of AS is a key factor in promoting cancer development. Compared with coding RNA, studies on the functions of long non-coding RNAs (lncRNAs) are far from enough. In fact, lncRNA is an important participant and regulator in the process of AS. On the one hand, lncRNAs regulate cancer progression as AS products of precursor messenger RNA (mRNA), but on the other hand, precursor lncRNA generates cancer-related abnormal splicing variants through AS. In addition, lncRNAs directly or indirectly regulate the AS events of downstream target genes, thus affecting the occurrence and development of cancer. Here, we reviewed how lncRNAs regulate AS and influence oncogenesis in different ways.

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          Alternative Isoform Regulation in Human Tissue Transcriptomes

          Through alternative processing of pre-mRNAs, individual mammalian genes often produce multiple mRNA and protein isoforms that may have related, distinct or even opposing functions. Here we report an in-depth analysis of 15 diverse human tissue and cell line transcriptomes based on deep sequencing of cDNA fragments, yielding a digital inventory of gene and mRNA isoform expression. Analysis of mappings of sequence reads to exon-exon junctions indicated that 92-94% of human genes undergo alternative splicing (AS), ∼86% with a minor isoform frequency of 15% or more. Differences in isoform-specific read densities indicated that a majority of AS and of alternative cleavage and polyadenylation (APA) events vary between tissues, while variation between individuals was ∼2- to 3-fold less common. Extreme or ‘switch-like’ regulation of splicing between tissues was associated with increased sequence conservation in regulatory regions and with generation of full-length open reading frames. Patterns of AS and APA were strongly correlated across tissues, suggesting coordinated regulation of these processes, and sequence conservation of a subset of known regulatory motifs in both alternative introns and 3′ UTRs suggested common involvement of specific factors in tissue-level regulation of both splicing and polyadenylation.
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            The landscape of long noncoding RNAs in the human transcriptome.

            Long noncoding RNAs (lncRNAs) are emerging as important regulators of tissue physiology and disease processes including cancer. To delineate genome-wide lncRNA expression, we curated 7,256 RNA sequencing (RNA-seq) libraries from tumors, normal tissues and cell lines comprising over 43 Tb of sequence from 25 independent studies. We applied ab initio assembly methodology to this data set, yielding a consensus human transcriptome of 91,013 expressed genes. Over 68% (58,648) of genes were classified as lncRNAs, of which 79% were previously unannotated. About 1% (597) of the lncRNAs harbored ultraconserved elements, and 7% (3,900) overlapped disease-associated SNPs. To prioritize lineage-specific, disease-associated lncRNA expression, we employed non-parametric differential expression testing and nominated 7,942 lineage- or cancer-associated lncRNA genes. The lncRNA landscape characterized here may shed light on normal biology and cancer pathogenesis and may be valuable for future biomarker development.
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              The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation.

              Alternative splicing (AS) of pre-mRNA is utilized by higher eukaryotes to achieve increased transcriptome and proteomic complexity. The serine/arginine (SR) splicing factors regulate tissue- or cell-type-specific AS in a concentration- and phosphorylation-dependent manner. However, the mechanisms that modulate the cellular levels of active SR proteins remain to be elucidated. In the present study, we provide evidence for a role for the long nuclear-retained regulatory RNA (nrRNA), MALAT1 in AS regulation. MALAT1 interacts with SR proteins and influences the distribution of these and other splicing factors in nuclear speckle domains. Depletion of MALAT1 or overexpression of an SR protein changes the AS of a similar set of endogenous pre-mRNAs. Furthermore, MALAT1 regulates cellular levels of phosphorylated forms of SR proteins. Taken together, our results suggest that MALAT1 regulates AS by modulating the levels of active SR proteins. Our results further highlight the role for an nrRNA in the regulation of gene expression. Copyright © 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                guocde@csu.edu.cn
                xiongwei@csu.edu.cn
                Journal
                Br J Cancer
                Br J Cancer
                British Journal of Cancer
                Nature Publishing Group UK (London )
                0007-0920
                1532-1827
                8 November 2021
                8 November 2021
                3 May 2022
                : 126
                : 8
                : 1113-1124
                Affiliations
                [1 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, , Central South University, ; Changsha, Hunan China
                [2 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, , Central South University, ; Changsha, Hunan China
                [3 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, the Third Xiangya Hospital, , Central South University, ; Changsha, Hunan China
                [4 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Department of Stomatology, Xiangya Hospital, , Central South University, ; Changsha, Hunan China
                [5 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Department of Oral and Maxillofacial Surgery, The Second Xiangya Hospital, , Central South University, ; Changsha, Hunan China
                [6 ]GRID grid.39382.33, ISNI 0000 0001 2160 926X, Department of Medicine, , Comprehensive Cancer Center Baylor College of Medicine, ; Houston, TX USA
                Author information
                http://orcid.org/0000-0002-0648-0565
                http://orcid.org/0000-0001-7414-2050
                http://orcid.org/0000-0003-1635-8173
                Article
                1600
                10.1038/s41416-021-01600-w
                9023592
                34750493
                029bf97a-9386-439b-97d4-4a678b10a989
                © The Author(s), under exclusive licence to Springer Nature Limited 2021

                Open AccessThis 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
                : 6 December 2020
                : 14 September 2021
                : 11 October 2021
                Funding
                Funded by: Funder:Natural Science Foundation of Hunan Province Grant Reference: 2019JJ50780
                Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);
                Award ID: 81803025
                Award ID: 82003243
                Award ID: 81972776
                Award ID: 82072374
                Award ID: 82073135
                Award Recipient :
                Funded by: Funder: Natural Science Foundation of Hunan Province Grant Reference Number: 2019JJ50354
                Funded by: Funder: Overseas Expertise Introduction Project for Discipline Innovation Grant Reference Number:111-2-12
                Categories
                Review Article
                Custom metadata
                © Springer Nature Limited 2022

                Oncology & Radiotherapy
                non-coding rnas,cancer genetics
                Oncology & Radiotherapy
                non-coding rnas, cancer genetics

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