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      Decoding m 6A mRNA methylation by reader proteins in liver diseases

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          Abstract

          N6-methyladenosine (m 6A) is a dynamic and reversible epigenetic regulation. As the most prevalent internal post-transcriptional modification in eukaryotic RNA, it participates in the regulation of gene expression through various mechanisms, such as mRNA splicing, nuclear export, localization, translation efficiency, mRNA stability, and structural transformation. The involvement of m6A in the regulation of gene expression depends on the specific recognition of m6A-modified RNA by reader proteins. In the pathogenesis and treatment of liver disease, studies have found that the expression levels of key genes that promote or inhibit the development of liver disease are regulated by m 6A modification, in which abnormal expression of reader proteins determines the fate of these gene transcripts. In this review, we introduce m 6A readers, summarize the recognition and regulatory mechanisms of m 6A readers on mRNA, and focus on the biological functions and mechanisms of m 6A readers in liver cancer, viral hepatitis, non-alcoholic fatty liver disease (NAFLD), hepatic fibrosis (HF), acute liver injury (ALI), and other liver diseases. This information is expected to be of high value to researchers deciphering the links between m 6A readers and human liver diseases.

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          Most cited references164

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          Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

          This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.
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            Hepatocellular carcinoma

            Hepatocellular carcinoma appears frequently in patients with cirrhosis. Surveillance by biannual ultrasound is recommended for such patients because it allows diagnosis at an early stage, when effective therapies are feasible. The best candidates for resection are patients with a solitary tumour and preserved liver function. Liver transplantation benefits patients who are not good candidates for surgical resection, and the best candidates are those within Milan criteria (solitary tumour ≤5 cm or up to three nodules ≤3 cm). Image-guided ablation is the most frequently used therapeutic strategy, but its efficacy is limited by the size of the tumour and its localisation. Chemoembolisation has survival benefit in asymptomatic patients with multifocal disease without vascular invasion or extrahepatic spread. Finally, sorafenib, lenvatinib, which is non-inferior to sorafenib, and regorafenib increase survival and are the standard treatments in advanced hepatocellular carcinoma. This Seminar summarises the scientific evidence that supports the current recommendations for clinical practice, and discusses the areas in which more research is needed.
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              Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq.

              An extensive repertoire of modifications is known to underlie the versatile coding, structural and catalytic functions of RNA, but it remains largely uncharted territory. Although biochemical studies indicate that N(6)-methyladenosine (m(6)A) is the most prevalent internal modification in messenger RNA, an in-depth study of its distribution and functions has been impeded by a lack of robust analytical methods. Here we present the human and mouse m(6)A modification landscape in a transcriptome-wide manner, using a novel approach, m(6)A-seq, based on antibody-mediated capture and massively parallel sequencing. We identify over 12,000 m(6)A sites characterized by a typical consensus in the transcripts of more than 7,000 human genes. Sites preferentially appear in two distinct landmarks--around stop codons and within long internal exons--and are highly conserved between human and mouse. Although most sites are well preserved across normal and cancerous tissues and in response to various stimuli, a subset of stimulus-dependent, dynamically modulated sites is identified. Silencing the m(6)A methyltransferase significantly affects gene expression and alternative splicing patterns, resulting in modulation of the p53 (also known as TP53) signalling pathway and apoptosis. Our findings therefore suggest that RNA decoration by m(6)A has a fundamental role in regulation of gene expression.
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                Author and article information

                Contributors
                Journal
                Genes Dis
                Genes Dis
                Genes & Diseases
                Chongqing Medical University
                2352-4820
                2352-3042
                13 April 2023
                March 2024
                13 April 2023
                : 11
                : 2
                : 711-726
                Affiliations
                [a ]Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, China
                [b ]The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei, Anhui 230032, China
                [c ]Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei, Anhui 230032, China
                [d ]Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
                [e ]Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230032, China
                Author notes
                []Corresponding author. Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, China. huanghuimin001s@ 123456qq.com lj@ 123456ahmu.edu.cn
                [1]

                These authors contributed equally to this work.

                Article
                S2352-3042(23)00148-4
                10.1016/j.gendis.2023.02.054
                10491919
                37692496
                d3992877-7081-4c69-a940-5e455aea3344
                © 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.

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

                History
                : 3 October 2022
                : 22 February 2023
                Categories
                Review Article

                igf2bps,liver diseases,m6a modification,m6a reader,mrna metabolism,yth domain protein

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