{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T22:24:48Z","timestamp":1792448688989,"version":"4.5.0"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T00:00:00Z","timestamp":1749686400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T00:00:00Z","timestamp":1749686400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of Hunan Province","doi-asserted-by":"publisher","award":["2025JJ60571"],"award-info":[{"award-number":["2025JJ60571"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of Hunan Province","doi-asserted-by":"publisher","award":["2020JJ5894"],"award-info":[{"award-number":["2020JJ5894"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2024M753695"],"award-info":[{"award-number":["2024M753695"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82070018"],"award-info":[{"award-number":["82070018"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81901664"],"award-info":[{"award-number":["81901664"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Med"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>METTL3, an m6A methyltransferase, enhances germinal center responses. This study explores its role in lupus B cells and its impact on B-cell activation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      METTL3 and m6A levels in B cells from systemic lupus erythematosus (SLE) patients and lupus-prone mice were analyzed using m6A dot blot, RT-qPCR, western blotting, and flow cytometry. B-cell activation and differentiation were induced with lipopolysaccharide (LPS). The effects of METTL3 overexpression or inhibition on B-cell maturation were assessed\n                      <jats:italic>in vivo<\/jats:italic>\n                      . In Raji B cells, METTL3 and PAX5 knockdowns were performed to examine their regulatory relationship. EMSA and dual-luciferase assays confirmed PAX5 binding to the METTL3 promoter, while RIP and actinomycin D assays evaluated METTL3\u2019s interaction with PAX5 mRNA. MeRIP-seq profiled m6A modifications across B-cell subsets.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      METTL3 expression and m6A levels were significantly elevated in B cells from SLE patients, with METTL3 levels positively correlating with disease activity. Elevated m6A and METTL3 levels were observed in both na\u00efve and activated B cells but decreased markedly during differentiation into ASCs, both\n                      <jats:italic>in vivo<\/jats:italic>\n                      and\n                      <jats:italic>in vitro<\/jats:italic>\n                      . MeRIP-seq analysis identified distinct m6A methylation patterns among B-cell subsets, particularly in key transcription factors critical for B-cell activation and differentiation. METTL3 facilitated pre-B cell development in bone marrow and maintained the balance of splenic B-cell subsets in mice. Furthermore, METTL3 preserved B-cell identity and enhanced activation. Mechanistically, METTL3 bound to\n                      <jats:italic>PAX5<\/jats:italic>\n                      mRNA, stabilizing it via m6A modification and promoting PAX5 expression. In turn, PAX5 directly bound to the\n                      <jats:italic>METTL3<\/jats:italic>\n                      promoter, driving its expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The elevated expression of METTL3 in lupus B cells is linked to the maintenance of autoreactive B-cell hyperresponsiveness, contributing to the pathogenesis of SLE. The reciprocal regulation between METTL3 and PAX5 highlights a critical mechanism underlying B-cell activation and persistence in autoimmune conditions like lupus.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s10020-025-01295-2","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T01:00:46Z","timestamp":1749690046000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Reciprocal METTL3-PAX5 regulation in maintaining B-cell identity and promoting B-cell hyperreactivity in SLE"],"prefix":"10.1186","volume":"31","author":[{"given":"Yiying","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shasha","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meidong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yisha","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxia","family":"Zuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huali","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muyao","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,12]]},"reference":[{"key":"1295_CR1","doi-asserted-by":"publisher","first-page":"102873","DOI":"10.1016\/j.jaut.2022.102873","volume":"132","author":"L Arbitman","year":"2022","unstructured":"Arbitman L, Furie R, Vashistha H. B cell-targeted therapies in systemic lupus erythematosus. J Autoimmun. 2022;132:102873.","journal-title":"J Autoimmun"},{"key":"1295_CR2","doi-asserted-by":"publisher","first-page":"1400","DOI":"10.1002\/art.40930","volume":"71","author":"M Aringer","year":"2019","unstructured":"Aringer M, et al. 2019 European league against rheumatism\/american college of rheumatology classification criteria for systemic lupus erythematosus. Arthritis Rheumatol. 2019;71:1400\u201312.","journal-title":"Arthritis Rheumatol"},{"key":"1295_CR3","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1038\/s41568-020-0253-2","volume":"20","author":"I Barbieri","year":"2020","unstructured":"Barbieri I, Kouzarides T. Role of RNA modifications in cancer. Nat Rev Cancer. 2020;20:303\u201322.","journal-title":"Nat Rev Cancer"},{"key":"1295_CR4","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1111\/j.1600-065X.2012.01112.x","volume":"247","author":"K Basso","year":"2012","unstructured":"Basso K, Dalla-Favera R. Roles of BCL6 in normal and transformed germinal center B cells. Immunol Rev. 2012;247:172\u201383.","journal-title":"Immunol Rev"},{"key":"1295_CR5","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1038\/ni1454","volume":"8","author":"C Cobaleda","year":"2007","unstructured":"Cobaleda C, Schebesta A, Delogu A, Busslinger M. Pax5: the guardian of B cell identity and function. Nat Immunol. 2007;8:463\u201370.","journal-title":"Nat Immunol"},{"key":"1295_CR6","doi-asserted-by":"publisher","unstructured":"Grenov AC, et al. The germinal center reaction depends on RNA Methylation and divergent functions of specific Methyl readers. J Exp Med. 2021;218. https:\/\/doi.org\/10.1084\/jem.20210360.","DOI":"10.1084\/jem.20210360"},{"key":"1295_CR7","doi-asserted-by":"publisher","first-page":"110778","DOI":"10.1016\/j.celrep.2022.110778","volume":"39","author":"A Grenov","year":"2022","unstructured":"Grenov A, Hezroni H, Lasman L, Hanna JH, Shulman Z. YTHDF2 suppresses the plasmablast genetic program and promotes germinal center formation. Cell Rep. 2022;39:110778.","journal-title":"Cell Rep"},{"key":"1295_CR8","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/j.coi.2006.01.007","volume":"18","author":"J Hagman","year":"2006","unstructured":"Hagman J, Lukin K. Transcription factors drive B cell development. Curr Opin Immunol. 2006;18:127\u201334.","journal-title":"Curr Opin Immunol"},{"key":"1295_CR9","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1186\/s13045-021-01129-8","volume":"14","author":"W Huang","year":"2021","unstructured":"Huang W, et al. N6-methyladenosine methyltransferases: functions, regulation, and clinical potential. J Hematol Oncol. 2021;14:117.","journal-title":"J Hematol Oncol"},{"key":"1295_CR10","doi-asserted-by":"publisher","first-page":"1924","DOI":"10.4049\/jimmunol.2101071","volume":"208","author":"H Huang","year":"2022","unstructured":"Huang H, et al. Mettl14-Mediated m6A modification is essential for germinal center B cell response. J Immunol. 2022;208:1924\u201336.","journal-title":"J Immunol"},{"key":"1295_CR11","doi-asserted-by":"publisher","unstructured":"Lou HT, Ling GS, Cao XT. Autoantibodies in systemic lupus erythematosus: from immunopathology to therapeutic target. J Autoimmun. 2022;132. https:\/\/doi.org\/10.1016\/j.jaut.2022.102861.","DOI":"10.1016\/j.jaut.2022.102861"},{"key":"1295_CR12","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1186\/s10020-023-00643-4","volume":"29","author":"S Lu","year":"2023","unstructured":"Lu S, et al. m6A methyltransferase METTL3 programs CD4\u2009+\u2009T-cell activation and effector T-cell differentiation in systemic lupus erythematosus. Mol Med. 2023;29:46.","journal-title":"Mol Med"},{"key":"1295_CR13","doi-asserted-by":"publisher","unstructured":"Ma K et al. Multiple functions of B cells in the pathogenesis of systemic lupus erythematosus. Int J Mol Sci. 2019;20. https:\/\/doi.org\/10.3390\/ijms20236021.","DOI":"10.3390\/ijms20236021"},{"key":"1295_CR14","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1038\/ni.3349","volume":"17","author":"M Minnich","year":"2016","unstructured":"Minnich M, et al. Multifunctional role of the transcription factor Blimp-1 in coordinating plasma cell differentiation. Nat Immunol. 2016;17:331\u201343.","journal-title":"Nat Immunol"},{"key":"1295_CR15","doi-asserted-by":"publisher","first-page":"2882","DOI":"10.4049\/jimmunol.1601863","volume":"200","author":"Y Miura","year":"2018","unstructured":"Miura Y, et al. Bach2 promotes B cell Receptor-Induced proliferation of B lymphocytes and represses Cyclin-Dependent kinase inhibitors. J Immunol. 2018;200:2882\u201393.","journal-title":"J Immunol"},{"key":"1295_CR16","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1038\/nri3795","volume":"15","author":"SL Nutt","year":"2015","unstructured":"Nutt SL, Hodgkin PD, Tarlinton DM, Corcoran LM. The generation of antibody-secreting plasma cells. Nat Rev Immunol. 2015;15:160\u201371.","journal-title":"Nat Rev Immunol"},{"key":"1295_CR17","doi-asserted-by":"publisher","first-page":"102627","DOI":"10.1016\/j.jaut.2021.102627","volume":"119","author":"AE Palm","year":"2021","unstructured":"Palm AE, Kleinau S. Marginal zone B cells: from housekeeping function to autoimmunity? J Autoimmun. 2021;119:102627.","journal-title":"J Autoimmun"},{"key":"1295_CR18","doi-asserted-by":"publisher","first-page":"2677","DOI":"10.1002\/art.34473","volume":"64","author":"M Petri","year":"2012","unstructured":"Petri M, et al. Derivation and validation of the systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012;64:2677\u201386.","journal-title":"Arthritis Rheum"},{"key":"1295_CR19","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1038\/nri.2017.24","volume":"17","author":"DJ Rawlings","year":"2017","unstructured":"Rawlings DJ, Metzler G, Wray-Dutra M, Jackson SW. Altered B cell signalling in autoimmunity. Nat Rev Immunol. 2017;17:421\u201336.","journal-title":"Nat Rev Immunol"},{"key":"1295_CR20","doi-asserted-by":"publisher","unstructured":"Scharer CD, Barwick BG, Guo MY, Bally APR, Boss JM. Plasma cell differentiation is controlled by multiple cell division-coupled epigenetic programs. Nat Commun. 2018;9. https:\/\/doi.org\/10.1038\/s41467-018-04125-8.","DOI":"10.1038\/s41467-018-04125-8"},{"key":"1295_CR21","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1016\/j.molcel.2023.01.006","volume":"83","author":"E Sendinc","year":"2023","unstructured":"Sendinc E, Shi Y. RNA m6A methylation across the transcriptome. Mol Cell. 2023;83:428\u201341.","journal-title":"Mol Cell"},{"key":"1295_CR22","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1038\/nri1572","volume":"5","author":"M Shapiro-Shelef","year":"2005","unstructured":"Shapiro-Shelef M, Calame K. Regulation of plasma-cell development. Nat Rev Immunol. 2005;5:230\u201342.","journal-title":"Nat Rev Immunol"},{"key":"1295_CR23","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1038\/s41590-020-0650-4","volume":"21","author":"Z Shulman","year":"2020","unstructured":"Shulman Z, Stern-Ginossar N. The RNA modification N-6-methyladenosine as a novel regulator of the immune system. Nat Immunol. 2020;21:501\u201312.","journal-title":"Nat Immunol"},{"key":"1295_CR24","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","volume":"102","author":"A Subramanian","year":"2005","unstructured":"Subramanian A, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102:15545\u201350.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"1295_CR25","doi-asserted-by":"publisher","unstructured":"Truffinet F et al. m6A RNA methylation controls salivary gland epithelial cell function and has a protective role in Sj\u00f6gren\u2019s disease. Ann Rheum Dis. 2024. https:\/\/doi.org\/10.1136\/ard-2024-226224.","DOI":"10.1136\/ard-2024-226224"},{"key":"1295_CR26","doi-asserted-by":"publisher","first-page":"2110","DOI":"10.1056\/NEJMra1100359","volume":"365","author":"GC Tsokos","year":"2011","unstructured":"Tsokos GC. Systemic lupus erythematosus. N Engl J Med. 2011;365:2110\u201321.","journal-title":"N Engl J Med"},{"key":"1295_CR27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/978-981-15-3532-1_1","volume":"1254","author":"Y Wang","year":"2020","unstructured":"Wang Y, Liu J, Burrows PD, Wang JY. B cell development and maturation. Adv Exp Med Biol. 2020a;1254:1\u201322.","journal-title":"Adv Exp Med Biol"},{"key":"1295_CR28","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1016\/j.it.2020.04.011","volume":"41","author":"H Wang","year":"2020","unstructured":"Wang H, Morse HC 3rd, Bolland S. Transcriptional control of mature B cell fates. Trends Immunol. 2020;41:601\u201313.","journal-title":"Trends Immunol"},{"key":"1295_CR29","doi-asserted-by":"publisher","unstructured":"Wang S, Li H, Lian Z, Deng S. The role of m6A modifications in B-Cell development and B-Cell-Related diseases. Int J Mol Sci. 2023;24. https:\/\/doi.org\/10.3390\/ijms24054721.","DOI":"10.3390\/ijms24054721"},{"key":"1295_CR30","doi-asserted-by":"publisher","first-page":"1002741","DOI":"10.3389\/fphar.2022.1002741","volume":"13","author":"Y Yang","year":"2022","unstructured":"Yang Y, Liu K, Liu M, Zhang H, Guo M. EZH2: its regulation and roles in immune disturbance of SLE. Front Pharmacol. 2022;13:1002741.","journal-title":"Front Pharmacol"},{"key":"1295_CR31","doi-asserted-by":"publisher","first-page":"110155","DOI":"10.1016\/j.intimp.2023.110155","volume":"119","author":"Y Yang","year":"2023","unstructured":"Yang Y, et al. EZH2 Inhibition dampens autoantibody production in lupus by restoring B cell immune tolerance. Int Immunopharmacol. 2023;119:110155.","journal-title":"Int Immunopharmacol"},{"key":"1295_CR32","doi-asserted-by":"publisher","first-page":"103341","DOI":"10.1016\/j.jaut.2024.103341","volume":"149","author":"Y Yang","year":"2024","unstructured":"Yang Y, et al. EZH2 promotes B-cell autoimmunity in primary sjogren\u2019s syndrome via METTL3-mediated m6A modification. J Autoimmun. 2024;149:103341.","journal-title":"J Autoimmun"},{"key":"1295_CR33","doi-asserted-by":"publisher","unstructured":"Yap DYH, Chan TM. B cell abnormalities in systemic lupus erythematosus and lupus Nephritis-Role in pathogenesis and effect of immunosuppressive treatments. Int J Mol Sci. 2019;20. https:\/\/doi.org\/10.3390\/ijms20246231.","DOI":"10.3390\/ijms20246231"},{"key":"1295_CR34","doi-asserted-by":"publisher","first-page":"1143","DOI":"10.1002\/art.41208","volume":"72","author":"M Zhang","year":"2020","unstructured":"Zhang M, et al. Methionine commits cells to differentiate into plasmablasts through epigenetic regulation of BTB and CNC homolog 2 by the methyltransferase EZH2. Arthritis Rheumatol. 2020;72:1143\u201353.","journal-title":"Arthritis Rheumatol"},{"key":"1295_CR35","doi-asserted-by":"publisher","first-page":"107819","DOI":"10.1016\/j.celrep.2020.107819","volume":"31","author":"Z Zheng","year":"2020","unstructured":"Zheng Z, et al. Control of early B cell development by the RNA N6-Methyladenosine methylation. Cell Rep. 2020;31:107819.","journal-title":"Cell Rep"}],"container-title":["Molecular Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s10020-025-01295-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s10020-025-01295-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s10020-025-01295-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T11:16:18Z","timestamp":1781608578000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s10020-025-01295-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,12]]},"references-count":35,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["1295"],"URL":"https:\/\/doi.org\/10.1186\/s10020-025-01295-2","relation":{},"ISSN":["1528-3658"],"issn-type":[{"value":"1528-3658","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,12]]},"assertion":[{"value":"3 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 June 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 June 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All experiments with human samples were approved by the Ethics Committee of Xiangya Hospital, Central South University (reference number:2019030465). All animal experiments were approved by the Ethical Committee for Animal Experiments of Central South University (reference number: 2020 sydw0950).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"236"}}