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      Role of m6A modification in female infertility and reproductive system diseases

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          Abstract

          Gamete abnormalities and reproductive system tumors have become a dominant cause of infertility, troubling people globally. In recent years, increasing evidence emerged and found that N6-methyladenosine (m6A) played a leading role in reproduction. The biological effects of m6A modification are dynamically and reversibly regulated by methyltransferases (writers), WTAP, METTL3, METTL14 and KIAA1429, demethylases (erasers), FTO and ALKBH5, and m6A binding proteins (readers), including YTH domain. In this review, we highlight the change of m6A modification in abnormal oogenesis, female reproductive system diseases including reproductive system tumors, adenomyosis, endometriosis, premature ovarian failure and polycystic ovary syndrome. Moreover, we review some of the mechanisms and the specific modified genes that have been identified. Especially, with the underlying mechanisms being uncovered, m6A and its protein machineries are expected to be the markers and targets for the diagnosis and treatment of female reproductive dysfunction.

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          ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility.

          Guanqun Zheng, John Dahl, Yamei Niu … (2013)
          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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            Recognition of RNA N 6 -methyladenosine by IGF2BP Proteins Enhances mRNA Stability and Translation

            Huilin Huang, Hengyou Weng, Wenju Sun … (2018)
            N 6-methyladenosine (m6A) is the most prevalent modification in eukaryotic messenger RNAs (mRNAs) and is interpreted by its readers, such as YTH domain-containing proteins, to regulate mRNA fate. Here we report the insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs; including IGF2BP1/2/3) as a distinct family of m6A readers that target thousands of mRNA transcripts through recognizing the consensus GG(m6A)C sequence. In contrast to the mRNA-decay-promoting function of YTHDF2, IGF2BPs promote the stability and storage of their target mRNAs (e.g., MYC) in an m6A-depedent manner under normal and stress conditions and thus affect gene expression output. Moreover, the K homology (KH) domains of IGF2BPs are required for their recognition of m6A and are critical for their oncogenic functions. Our work therefore reveals a different facet of the m6A-reading process that promotes mRNA stability and translation, and highlights the functional importance of IGF2BPs as m6A readers in post-transcriptional gene regulation and cancer biology.
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              MODOMICS: a database of RNA modification pathways. 2017 update

              Pietro Boccaletto, Magdalena A. Machnicka, Elzbieta Purta … (2017)
              Abstract MODOMICS is a database of RNA modifications that provides comprehensive information concerning the chemical structures of modified ribonucleosides, their biosynthetic pathways, the location of modified residues in RNA sequences, and RNA-modifying enzymes. In the current database version, we included the following new features and data: extended mass spectrometry and liquid chromatography data for modified nucleosides; links between human tRNA sequences and MINTbase - a framework for the interactive exploration of mitochondrial and nuclear tRNA fragments; new, machine-friendly system of unified abbreviations for modified nucleoside names; sets of modified tRNA sequences for two bacterial species, updated collection of mammalian tRNA modifications, 19 newly identified modified ribonucleosides and 66 functionally characterized proteins involved in RNA modification. Data from MODOMICS have been linked to the RNAcentral database of RNA sequences. MODOMICS is available at http://modomics.genesilico.pl.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Biol Sci
                Journal ID (iso-abbrev): Int J Biol Sci
                Journal ID (publisher-id): ijbs
                Title: International Journal of Biological Sciences
                Publisher: Ivyspring International Publisher (Sydney )
                ISSN (Electronic): 1449-2288
                Publication date Collection: 2022
                Publication date (Electronic): 16 May 2022
                Volume: 18
                Issue: 9
                Pages: 3592-3604
                Affiliations
                Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P.R. China.
                Author notes
                ✉ Corresponding author: Yiwei Fang, evayfang@ 123456163.com

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                Publisher ID: ijbsv18p3592
                DOI: 10.7150/ijbs.69771
                PMC ID: 9254474
                PubMed ID: 35813486
                SO-VID: bb3a4d16-05ca-44f4-8274-5a293152ba8c
                Copyright © © The author(s)
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                History
                Date received : 6 December 2021
                Date accepted : 22 April 2022
                Categories
                Subject: Review

                ScienceOpen disciplines: Life sciences
                Keywords: rna modification,n6-methyladenosine,female reproductive diseases,infertility,reproductive system neoplasms
                Data availability:
                ScienceOpen disciplines: Life sciences
                Keywords: rna modification, n6-methyladenosine, female reproductive diseases, infertility, reproductive system neoplasms

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