Dynamic MA MRNA Methylation Reveals the Role of METTL3/14-mA-MNK2-ERK Signaling Axis in Skeletal Muscle Differentiation and Regeneration

Overview

Journal Front Cell Dev Biol

Specialty Cell Biology

Date 2021 Oct 18

PMID 34660602

Citations 16

Authors

Shu-Juan Xie

Hang Lei

Bing Yang

Li-Ting Diao

Jian-You Liao

Jie-Hua He

Shuang Tao

Yan-Xia Hu

Ya-Rui Hou

Yu-Jia Sun

Yan-Wen Peng

Qi Zhang

Zhen-Dong Xiao

Affiliations

Soon will be listed here.

Abstract

N-methyladenosine (mA) RNA methylation has emerged as an important factor in various biological processes by regulating gene expression. However, the dynamic profile, function and underlying molecular mechanism of mA modification during skeletal myogenesis remain elusive. Here, we report that members of the mA core methyltransferase complex, METTL3 and METTL14, are downregulated during skeletal muscle development. Overexpression of either METTL3 or METTL14 dramatically blocks myotubes formation. Correspondingly, knockdown of METTL3 or METTL14 accelerates the differentiation of skeletal muscle cells. Genome-wide transcriptome analysis suggests ERK/MAPK is the downstream signaling pathway that is regulated to the greatest extent by METTL3/METTL14. Indeed, METTL3/METTL14 expression facilitates ERK/MAPK signaling. Via MeRIP-seq, we found that MNK2, a critical regulator of ERK/MAPK signaling, is mA modified and is a direct target of METTL3/METTL14. We further revealed that YTHDF1 is a potential reader of mA on MNK2, regulating MNK2 protein levels without affecting mRNA levels. Furthermore, we discovered that METTL3/14-MNK2 axis was up-regulated notably after acute skeletal muscle injury. Collectively, our studies revealed that the mA writers METTL3/METTL14 and the mA reader YTHDF1 orchestrate MNK2 expression posttranscriptionally and thus control ERK signaling, which is required for the maintenance of muscle myogenesis and may contribute to regeneration.

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References

Shi H, Wei J, He C . Where, When, and How: Context-Dependent Functions of RNA Methylation Writers, Readers, and Erasers. Mol Cell. 2019; 74(4):640-650. PMC: 6527355. DOI: 10.1016/j.molcel.2019.04.025. View

Xie S, Li J, Chen H, Tan Y, Liu S, Zhang Y . Inhibition of the JNK/MAPK signaling pathway by myogenesis-associated miRNAs is required for skeletal muscle development. Cell Death Differ. 2018; 25(9):1581-1597. PMC: 6143622. DOI: 10.1038/s41418-018-0063-1. View

Diao L, Xie S, Lei H, Qiu X, Huang M, Tao S . METTL3 regulates skeletal muscle specific miRNAs at both transcriptional and post-transcriptional levels. Biochem Biophys Res Commun. 2021; 552:52-58. DOI: 10.1016/j.bbrc.2021.03.035. View

Zhao X, Yang Y, Sun B, Shi Y, Yang X, Xiao W . FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis. Cell Res. 2014; 24(12):1403-19. PMC: 4260349. DOI: 10.1038/cr.2014.151. View

Shang M, Cappellesso F, Amorim R, Serneels J, Virga F, Eelen G . Macrophage-derived glutamine boosts satellite cells and muscle regeneration. Nature. 2020; 587(7835):626-631. PMC: 7116844. DOI: 10.1038/s41586-020-2857-9. View

Wang Y, Gao M, Zhu F, Li X, Yang Y, Yan Q . METTL3 is essential for postnatal development of brown adipose tissue and energy expenditure in mice. Nat Commun. 2020; 11(1):1648. PMC: 7125133. DOI: 10.1038/s41467-020-15488-2. View

Alarcon C, Lee H, Goodarzi H, Halberg N, Tavazoie S . N6-methyladenosine marks primary microRNAs for processing. Nature. 2015; 519(7544):482-5. PMC: 4475635. DOI: 10.1038/nature14281. View

Meyer K, Jaffrey S . Rethinking mA Readers, Writers, and Erasers. Annu Rev Cell Dev Biol. 2017; 33:319-342. PMC: 5963928. DOI: 10.1146/annurev-cellbio-100616-060758. View

Knuckles P, Lence T, Haussmann I, Jacob D, Kreim N, Carl S . Zc3h13/Flacc is required for adenosine methylation by bridging the mRNA-binding factor Rbm15/Spenito to the mA machinery component Wtap/Fl(2)d. Genes Dev. 2018; 32(5-6):415-429. PMC: 5900714. DOI: 10.1101/gad.309146.117. View

10.

Ueda T, Sasaki M, Elia A, Chio I, Hamada K, Fukunaga R . Combined deficiency for MAP kinase-interacting kinase 1 and 2 (Mnk1 and Mnk2) delays tumor development. Proc Natl Acad Sci U S A. 2010; 107(32):13984-90. PMC: 2922567. DOI: 10.1073/pnas.1008136107. View

11.

Zhang W, He L, Liu Z, Ren X, Qi L, Wan L . Multifaceted Functions and Novel Insight Into the Regulatory Role of RNA N-Methyladenosine Modification in Musculoskeletal Disorders. Front Cell Dev Biol. 2020; 8:870. PMC: 7493464. DOI: 10.3389/fcell.2020.00870. View

12.

Wang P, Doxtader K, Nam Y . Structural Basis for Cooperative Function of Mettl3 and Mettl14 Methyltransferases. Mol Cell. 2016; 63(2):306-317. PMC: 4958592. DOI: 10.1016/j.molcel.2016.05.041. View

13.

Waskiewicz A, Flynn A, Proud C, Cooper J . Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2. EMBO J. 1997; 16(8):1909-20. PMC: 1169794. DOI: 10.1093/emboj/16.8.1909. View

14.

Michailovici I, Harrington H, Azogui H, Yahalom-Ronen Y, Plotnikov A, Ching S . Nuclear to cytoplasmic shuttling of ERK promotes differentiation of muscle stem/progenitor cells. Development. 2014; 141(13):2611-20. PMC: 4067960. DOI: 10.1242/dev.107078. View

15.

Gheller B, Blum J, Fong E, Malysheva O, Cosgrove B, Thalacker-Mercer A . A defined N6-methyladenosine (mA) profile conferred by METTL3 regulates muscle stem cell/myoblast state transitions. Cell Death Discov. 2020; 6(1):95. PMC: 7524727. DOI: 10.1038/s41420-020-00328-5. View

16.

Yohe M, Gryder B, Shern J, Song Y, Chou H, Sindiri S . MEK inhibition induces MYOG and remodels super-enhancers in RAS-driven rhabdomyosarcoma. Sci Transl Med. 2018; 10(448). PMC: 8054766. DOI: 10.1126/scitranslmed.aan4470. View

17.

Wang X, Huang N, Yang M, Wei D, Tai H, Han X . FTO is required for myogenesis by positively regulating mTOR-PGC-1α pathway-mediated mitochondria biogenesis. Cell Death Dis. 2017; 8(3):e2702. PMC: 5386528. DOI: 10.1038/cddis.2017.122. View

18.

Wu H, Hu C, Wang A, Weisberg E, Chen Y, Yun C . Discovery of a BTK/MNK dual inhibitor for lymphoma and leukemia. Leukemia. 2015; 30(1):173-81. PMC: 4987129. DOI: 10.1038/leu.2015.180. View

19.

Yang Y, Hsu P, Chen Y, Yang Y . Dynamic transcriptomic mA decoration: writers, erasers, readers and functions in RNA metabolism. Cell Res. 2018; 28(6):616-624. PMC: 5993786. DOI: 10.1038/s41422-018-0040-8. View

20.

Tan Y, Zhang Y, Li B, Ou Y, Xie S, Chen P . PERK Signaling Controls Myoblast Differentiation by Regulating MicroRNA Networks. Front Cell Dev Biol. 2021; 9:670435. PMC: 8193987. DOI: 10.3389/fcell.2021.670435. View