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      LncRNA-mediated DNA methylation: an emerging mechanism in cancer and beyond

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          Abstract

          DNA methylation is one of the most important epigenetic mechanisms to regulate gene expression, which is highly dynamic during development and specifically maintained in somatic cells. Aberrant DNA methylation patterns are strongly associated with human diseases including cancer. How are the cell-specific DNA methylation patterns established or disturbed is a pivotal question in developmental biology and cancer epigenetics. Currently, compelling evidence has emerged that long non-coding RNA (lncRNA) mediates DNA methylation in both physiological and pathological conditions. In this review, we provide an overview of the current understanding of lncRNA-mediated DNA methylation, with emphasis on the roles of this mechanism in cancer, which to the best of our knowledge, has not been systematically summarized. In addition, we also discuss the potential clinical applications of this mechanism in RNA-targeting drug development.

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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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            Landscape of transcription in human cells

            Summary Eukaryotic cells make many types of primary and processed RNAs that are found either in specific sub-cellular compartments or throughout the cells. A complete catalogue of these RNAs is not yet available and their characteristic sub-cellular localizations are also poorly understood. Since RNA represents the direct output of the genetic information encoded by genomes and a significant proportion of a cell’s regulatory capabilities are focused on its synthesis, processing, transport, modifications and translation, the generation of such a catalogue is crucial for understanding genome function. Here we report evidence that three quarters of the human genome is capable of being transcribed, as well as observations about the range and levels of expression, localization, processing fates, regulatory regions and modifications of almost all currently annotated and thousands of previously unannotated RNAs. These observations taken together prompt to a redefinition of the concept of a gene.
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              The emerging role of lncRNAs in cancer.

              It is increasingly evident that many of the genomic mutations in cancer reside inside regions that do not encode proteins. However, these regions are often transcribed into long noncoding RNAs (lncRNAs). The recent application of next-generation sequencing to a growing number of cancer transcriptomes has indeed revealed thousands of lncRNAs whose aberrant expression is associated with different cancer types. Among the few that have been functionally characterized, several have been linked to malignant transformation. Notably, these lncRNAs have key roles in gene regulation and thus affect various aspects of cellular homeostasis, including proliferation, survival, migration or genomic stability. This review aims to summarize current knowledge of lncRNAs from the cancer perspective. It discusses the strategies that led to the identification of cancer-related lncRNAs and the methodologies and challenges involving the study of these molecules, as well as the imminent applications of these findings to the clinic.
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                Author and article information

                Contributors
                huangwx@syphu.edu.cn
                xw_kanion@163.com
                Journal
                J Exp Clin Cancer Res
                J Exp Clin Cancer Res
                Journal of Experimental & Clinical Cancer Research : CR
                BioMed Central (London )
                0392-9078
                1756-9966
                15 March 2022
                15 March 2022
                2022
                : 41
                : 100
                Affiliations
                [1 ]GRID grid.412561.5, ISNI 0000 0000 8645 4345, Wuya College of Innovation, Shenyang Pharmaceutical University, ; Shenyang, 110016 Liaoning China
                [2 ]GRID grid.410737.6, ISNI 0000 0000 8653 1072, The Fifth Affiliated Hospital of Guangzhou Medical University, ; Guangzhou, 510700 Guangdong China
                [3 ]GRID grid.452789.5, State Key Laboratory of New-Tech for Chinese Medicine Pharmaceutical Process, ; Lianyungang, 222001 Jiangsu China
                [4 ]GRID grid.412636.4, ISNI 0000 0004 1757 9485, Department of Laboratory Medicine, , The First Affiliated Hospital of China Medical University, ; Shenyang, 110001 Liaoning China
                [5 ]GRID grid.452789.5, Jiangsu Kanion Pharmaceutical CO. LTD, ; Lianyungang, 222001 Jiangsu China
                [6 ]GRID grid.7597.c, ISNI 0000000094465255, Center for Biosystems Dynamics Research, , RIKEN, ; 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 Japan
                Author information
                http://orcid.org/0000-0002-9159-3678
                Article
                2319
                10.1186/s13046-022-02319-z
                8922926
                35292092
                2b9b3928-820c-4bb7-b471-4a5145ac4da7
                © The Author(s) 2022

                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/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 6 January 2022
                : 8 March 2022
                Funding
                Funded by: Xingliao Talents Program
                Award ID: XLYC1802007
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 32000426
                Award ID: 31971335
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100012165, Key Technologies Research and Development Program;
                Award ID: 2021YFC2009302
                Award Recipient :
                Funded by: Special Funds for Transformation and Upgrading of Industrial Informatization of Industry and Information Technology Department of Jiangsu in 2020
                Funded by: FundRef http://dx.doi.org/10.13039/501100007620, Department of Education of Liaoning Province;
                Award ID: 1911520092
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2022

                Oncology & Radiotherapy
                lncrna,dna methylation,non-coding rna,dnmt,tet,cancer
                Oncology & Radiotherapy
                lncrna, dna methylation, non-coding rna, dnmt, tet, cancer

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