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      Epigenetics: Roles and therapeutic implications of non-coding RNA modifications in human cancers

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          Abstract

          As next-generation sequencing (NGS) is leaping forward, more than 160 covalent RNA modification processes have been reported, and they are widely present in every organism and overall RNA type. Many modification processes of RNA introduce a new layer to the gene regulation process, resulting in novel RNA epigenetics. The commonest RNA modification includes pseudouridine (Ψ), N 7-methylguanosine (m7G), 5-hydroxymethylcytosine (hm5C), 5-methylcytosine (m5C), N 1-methyladenosine (m1A), N 6-methyladenosine (m6A), and others. In this study, we focus on non-coding RNAs (ncRNAs) to summarize the epigenetic consequences of RNA modifications, and the pathogenesis of cancer, as diagnostic markers and therapeutic targets for cancer, as well as the mechanisms affecting the immune environment of cancer. In addition, we summarize the current status of epigenetic drugs for tumor therapy based on ncRNA modifications and the progress of bioinformatics methods in elucidating RNA modifications in recent years.

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          Abstract

          In this review, Rong et al. focus on ncRNAs to summarize the epigenetic consequences of RNA modification, and the pathogenesis of cancer, as diagnostic markers and therapeutic targets for cancer, as well as the mechanisms affecting the immune environment of cancer.

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          Most cited references170

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          Integrative analysis of 111 reference human epigenomes

          The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but a similar reference has lacked for epigenomic studies. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection to-date of human epigenomes for primary cells and tissues. Here, we describe the integrative analysis of 111 reference human epigenomes generated as part of the program, profiled for histone modification patterns, DNA accessibility, DNA methylation, and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically-relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation, and human disease.
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            N6-Methyladenosine in Nuclear RNA is a Major Substrate of the Obesity-Associated FTO

            We report here that FTO (fat mass and obesity-associated protein) exhibits efficient oxidative demethylation activity of abundant N 6-methyladenosine (m6A) residues in RNA in vitro. FTO knockdown with siRNA led to an increased level of m6A in mRNA, whereas overexpression of FTO resulted in a decreased level of m6A in human cells. We further show that FTO partially colocalizes with nuclear speckles, supporting m6A in nuclear RNA as a physiological substrate of FTO.
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              ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility.

              N(6)-methyladenosine (m(6)A) is the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes. Here we report ALKBH5 as another mammalian demethylase that oxidatively reverses m(6)A in mRNA in vitro and in vivo. This demethylation activity of ALKBH5 significantly affects mRNA export and RNA metabolism as well as the assembly of mRNA processing factors in nuclear speckles. Alkbh5-deficient male mice have increased m(6)A in mRNA and are characterized by impaired fertility resulting from apoptosis that affects meiotic metaphase-stage spermatocytes. In accordance with this defect, we have identified in mouse testes 1,551 differentially expressed genes that cover broad functional categories and include spermatogenesis-related mRNAs involved in the p53 functional interaction network. The discovery of this RNA demethylase strongly suggests that the reversible m(6)A modification has fundamental and broad functions in mammalian cells. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Mol Ther Nucleic Acids
                Mol Ther Nucleic Acids
                Molecular Therapy. Nucleic Acids
                American Society of Gene & Cell Therapy
                2162-2531
                01 May 2021
                03 September 2021
                01 May 2021
                : 25
                : 67-82
                Affiliations
                [1 ]Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Transplantation, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China
                [2 ]Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
                Author notes
                []Corresponding author :Xuehao Wang, MD, Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Transplantation, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China. wangxh@ 123456njmu.edu.cn
                [∗∗ ]Corresponding author: Weiwei Tang, MD, Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Transplantation, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China. 1243773473twww@ 123456sina.com
                [∗∗∗ ]Corresponding author: Chuanyong Zhang, MD, Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Transplantation, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China. zcy13951673178@ 123456163.com
                [3]

                These authors contributed equally

                Article
                S2162-2531(21)00115-3
                10.1016/j.omtn.2021.04.021
                8217334
                34188972
                841bc6a3-875e-4c76-80b5-b5e86ef8f5a2
                © 2021 The Authors.

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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                Categories
                Review

                Molecular medicine
                epigenetics,rna modifications,cancer,non-coding rnas,immune,target therapy
                Molecular medicine
                epigenetics, rna modifications, cancer, non-coding rnas, immune, target therapy

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