Overview of Distinct N6-Methyladenosine Profiles of Messenger RNA in Osteoarthritis

Overview

Journal Front Genet

Date 2023 May 25

PMID 37229206

Authors

Yang Yu

Shitao Lu

Yu Li

Jianzhong Xu

Affiliations

Soon will be listed here.

Abstract

Although N6-methyladenosine (m6A) modification is closely associated with the pathogenesis of osteoarthritis (OA), the mRNA profile of m6A modification in OA remains unknown. Therefore, our study aimed to identify common m6A features and novel m6A-related therapeutic targets in OA. In the present study, we identified 3962 differentially methylated genes (DMGs) and 2048 differentially expressed genes (DEGs) using methylated RNA immunoprecipitation next-generation sequencing (MeRIP-seq) and RNA-sequencing. A co-expression analysis of DMGs and DEGs showed that the expression of 805 genes was significantly affected by m6A methylation. Specifically, we obtained 28 hypermethylated and upregulated genes, 657 hypermethylated and downregulated genes, 102 hypomethylated and upregulated genes, and 18 hypomethylated and downregulated genes. The differential gene expression analysis based on GSE114007 revealed 2770 DEGs. The Weighted Gene Co-expression Network Analysis (WGCNA) based on GSE114007 identified 134 OA-related genes. By taking the intersection of these results, ten novel aberrantly expressed, m6A-modified and OA-related key genes were identified, including SKP2, SULF1, TNC, ZFP36, CEBPB, BHLHE41, SOX9, VEGFA, MKNK2 and TUBB4B. The present study may provide valuable insight into identifying m6A-related pharmacological targets in OA.

Citing Articles

Elucidating the role of ubiquitination and deubiquitination in osteoarthritis progression.

Zheng C, Chen J, Wu Y, Wang X, Lin Y, Shu L Front Immunol. 2023; 14:1217466.

PMID: 37359559 PMC: 10288844. DOI: 10.3389/fimmu.2023.1217466.

References

Otsuki S, Hanson S, Miyaki S, Grogan S, Kinoshita M, Asahara H . Extracellular sulfatases support cartilage homeostasis by regulating BMP and FGF signaling pathways. Proc Natl Acad Sci U S A. 2010; 107(22):10202-7. PMC: 2890424. DOI: 10.1073/pnas.0913897107. View

Chen X, Gong W, Shao X, Shi T, Zhang L, Dong J . METTL3-mediated mA modification of ATG7 regulates autophagy-GATA4 axis to promote cellular senescence and osteoarthritis progression. Ann Rheum Dis. 2021; 81(1):87-99. DOI: 10.1136/annrheumdis-2021-221091. View

Zhang H, Huang T, Ren X, Fang X, Chen X, Wei H . Integrated pan-cancer analysis of CSMD2 as a potential prognostic, diagnostic, and immune biomarker. Front Genet. 2022; 13:918486. PMC: 9428318. DOI: 10.3389/fgene.2022.918486. View

Liang C, Liang G, Zheng X, Huang Y, Huang S, Yin D . RSP5 Positively Regulates the Osteogenic Differentiation of Mesenchymal Stem Cells by Activating the K63-Linked Ubiquitination of Akt. Stem Cells Int. 2020; 2020:7073805. PMC: 7165343. DOI: 10.1155/2020/7073805. View

Liu Q, Li M, Jiang L, Jiang R, Fu B . METTL3 promotes experimental osteoarthritis development by regulating inflammatory response and apoptosis in chondrocyte. Biochem Biophys Res Commun. 2019; 516(1):22-27. DOI: 10.1016/j.bbrc.2019.05.168. View

Liu K, Ouyang Q, Zhan Y, Yin H, Liu B, Tan L . Pharmacoepitranscriptomic landscape revealing m6A modification could be a drug-effect biomarker for cancer treatment. Mol Ther Nucleic Acids. 2022; 28:464-476. PMC: 9044172. DOI: 10.1016/j.omtn.2022.04.001. View

Wang G, Chan C, Gao Y, Lin H . Novel roles of Skp2 E3 ligase in cellular senescence, cancer progression, and metastasis. Chin J Cancer. 2011; 31(4):169-77. PMC: 3777478. DOI: 10.5732/cjc.011.10319. View

Tong J, Deng C, Sun G, Zhou J, Zhong P, Wang T . Electroacupuncture Upregulates HIF-1 and SOX9 Expression in Knee Osteoarthritis. Evid Based Complement Alternat Med. 2021; 2021:2047097. PMC: 8575628. DOI: 10.1155/2021/2047097. View

Sang W, Xue S, Jiang Y, Lu H, Zhu L, Wang C . METTL3 involves the progression of osteoarthritis probably by affecting ECM degradation and regulating the inflammatory response. Life Sci. 2021; 278:119528. DOI: 10.1016/j.lfs.2021.119528. View

10.

Malki S, Nef S, Notarnicola C, Thevenet L, Gasca S, Mejean C . Prostaglandin D2 induces nuclear import of the sex-determining factor SOX9 via its cAMP-PKA phosphorylation. EMBO J. 2005; 24(10):1798-809. PMC: 1142593. DOI: 10.1038/sj.emboj.7600660. View

11.

He Y, Wang W, Xu X, Yang B, Yu X, Wu Y . Mettl3 inhibits the apoptosis and autophagy of chondrocytes in inflammation through mediating Bcl2 stability via Ythdf1-mediated mA modification. Bone. 2021; 154:116182. DOI: 10.1016/j.bone.2021.116182. View

12.

Xu L, Wu Z, He Y, Chen Z, Xu K, Yu W . MFN2 contributes to metabolic disorders and inflammation in the aging of rat chondrocytes and osteoarthritis. Osteoarthritis Cartilage. 2020; 28(8):1079-1091. DOI: 10.1016/j.joca.2019.11.011. View

13.

Bechara R, Amatya N, Bailey R, Li Y, Aggor F, Li D . The mA reader IMP2 directs autoimmune inflammation through an IL-17- and TNFα-dependent C/EBP transcription factor axis. Sci Immunol. 2021; 6(61). PMC: 8404281. DOI: 10.1126/sciimmunol.abd1287. View

14.

Zhang G, Wang T, Huang Z, Chen Y, Sun L, Xia X . METTL3 dual regulation of the stability of LINC00662 and VEGFA RNAs promotes colorectal cancer angiogenesis. Discov Oncol. 2022; 13(1):89. PMC: 9482670. DOI: 10.1007/s12672-022-00557-3. View

15.

Ren J, Li Y, Wuermanbieke S, Hu S, Huang G . N-methyladenosine (mA) methyltransferase METTL3-mediated LINC00680 accelerates osteoarthritis through mA/SIRT1 manner. Cell Death Discov. 2022; 8(1):240. PMC: 9061755. DOI: 10.1038/s41420-022-00890-0. View

16.

Ianniello Z, Paiardini A, Fatica A . N-Methyladenosine (mA): A Promising New Molecular Target in Acute Myeloid Leukemia. Front Oncol. 2019; 9:251. PMC: 6465620. DOI: 10.3389/fonc.2019.00251. View

17.

Yang L, Ren Z, Yan S, Zhao L, Liu J, Zhao L . Nsun4 and Mettl3 mediated translational reprogramming of Sox9 promotes BMSC chondrogenic differentiation. Commun Biol. 2022; 5(1):495. PMC: 9133052. DOI: 10.1038/s42003-022-03420-x. View

18.

Peat G, Thomas M . Osteoarthritis year in review 2020: epidemiology & therapy. Osteoarthritis Cartilage. 2020; 29(2):180-189. DOI: 10.1016/j.joca.2020.10.007. View

19.

Jiang X, Liu B, Nie Z, Duan L, Xiong Q, Jin Z . The role of m6A modification in the biological functions and diseases. Signal Transduct Target Ther. 2021; 6(1):74. PMC: 7897327. DOI: 10.1038/s41392-020-00450-x. View

20.

Liu X, He H, Zhang F, Hu X, Bi F, Li K . m6A methylated EphA2 and VEGFA through IGF2BP2/3 regulation promotes vasculogenic mimicry in colorectal cancer via PI3K/AKT and ERK1/2 signaling. Cell Death Dis. 2022; 13(5):483. PMC: 9122982. DOI: 10.1038/s41419-022-04950-2. View