{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T13:17:50Z","timestamp":1775308670529,"version":"3.50.1"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,10,4]],"date-time":"2021-10-04T00:00:00Z","timestamp":1633305600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Atrial fibrillation (AF)\/paroxysmal AF (PAF) is the main cause of cardiogenic embolism. In recent years, the progression from paroxysmal AF to persistent AF has attracted more and more attention. However, the molecular mechanism of the progression of AF is unclear. In this study, we performed RNA sequencing for normal samples, paroxysmal AF and persistent AF samples to identify differentially expressed gene (DEG) and explore the roles of these DEGs in AF. Totally, 272 differently expressed mRNAs (DEmRNAs) and 286 differentially expressed lncRNAs (DElncRNAs) were identified in paroxysmal AF compared to normal samples; 324 DEmRNAs and 258 DElncRNAs were found in persistent atrial fibrillation compared with normal samples; and 520 DEmRNAs and 414 DElncRNAs were identified in persistent AF compared to paroxysmal AF samples. Interestingly, among the DEGs, approximately 50% were coding genes and around 50% were non-coding RNAs, suggesting that lncRNAs may also have a crucial role in the progression of AF. Bioinformatics analysis demonstrated that these DEGs were significantly related to regulating multiple AF associated pathways, such as the regulation of vascular endothelial growth factor production and binding to the CXCR chemokine receptor. Furthermore, weighted gene co-expression network analysis (WGCNA) was conducted to identify key modules and hub RNAs and lncRNAs to determine their potential associations with AF. Five hub modules were identified in the progression of AF, including blue, brown, gray, turquoise and yellow modules. Interestingly, blue module and turquoise module were significantly negatively and positively correlated to the progression of AF respectively, indicating that they may have a more important role in the AF. Moreover, the hub protein-protein interaction (PPI) networks and lncRNA\u2013mRNA regulatory network were constructed. Bioinformatics analysis on the hub PPI network in turquoise was involved in regulating immune response related signaling, such as leukocyte chemotaxis, macrophage activation, and positive regulation of \u03b1-\u03b2 T cell activation. Our findings could clarify the underlying molecular changes associated fibrillation, and provide a useful resource for identifying AF marker.<\/jats:p>","DOI":"10.3389\/fcell.2021.722671","type":"journal-article","created":{"date-parts":[[2021,10,4]],"date-time":"2021-10-04T05:42:31Z","timestamp":1633326151000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Identification of Hub mRNAs and lncRNAs in Atrial Fibrillation Using Weighted Co-expression Network Analysis With RNA-Seq Data"],"prefix":"10.3389","volume":"9","author":[{"given":"Pan","family":"Yang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yujing","family":"Cao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huagang","family":"Jian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,10,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1048","DOI":"10.1111\/ene.12577","article-title":"Association of improved outcome in acute ischaemic stroke patients with atrial fibrillation who receive early antithrombotic therapy: analysis from VISTA.","volume":"22","author":"Abdul-Rahim","year":"2015","journal-title":"Eur. J. Neurol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"2010","DOI":"10.1016\/j.jacc.2013.06.052","article-title":"Mutation E169K in junctophilin-2 causes atrial fibrillation due to impaired RyR2 stabilization.","volume":"62","author":"Beavers","year":"2013","journal-title":"J. Am. Coll. Cardiol."},{"key":"B3","first-page":"12878","article-title":"Long noncoding RNA XIST regulates cardiomyocyte apoptosis by targeting miR-873-5p\/MCL1 axis.","volume":"24","author":"Cai","year":"2020","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"B4","doi-asserted-by":"crossref","DOI":"10.1186\/s10020-019-0074-5","article-title":"LncRNA PVT1 regulates atrial fibrosis via miR-128-3p-SP1-TGF-beta1-Smad axis in atrial fibrillation.","volume":"25","author":"Cao","year":"2019","journal-title":"Mol. Med."},{"key":"B5","doi-asserted-by":"crossref","DOI":"10.1186\/1480-9222-16-11","article-title":"The functional role of long non-coding RNAs and epigenetics.","volume":"16","author":"Cao","year":"2014","journal-title":"Biol. Proced. Online"},{"key":"B6","doi-asserted-by":"publisher","first-page":"2187","DOI":"10.1161\/01.str.0000023889.84649.3d","article-title":"Is the hypercoagulable state in atrial fibrillation mediated by vascular endothelial growth factor?","volume":"33","author":"Chung","year":"2002","journal-title":"Stroke"},{"key":"B7","doi-asserted-by":"publisher","first-page":"107","DOI":"10.15420\/cfr.2018.19.2","article-title":"Exercise training in heart failure patients with persistent atrial fibrillation: a practical approach.","volume":"4","author":"Cornelis","year":"2018","journal-title":"Card Fail Rev."},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.647124","article-title":"LncRNA nuclear-enriched abundant transcript 1 regulates atrial fibrosis via the miR-320\/NPAS2 axis in atrial fibrillation.","volume":"12","author":"Dai","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B9","doi-asserted-by":"crossref","DOI":"10.1155\/2020\/5925342","article-title":"Long Noncoding RNA HOTAIR functions as a competitive endogenous RNA to Regulate Connexin43 remodeling in atrial fibrillation by sponging MicroRNA-613.","volume":"2020","author":"Dai","year":"2020","journal-title":"Cardiovasc. Ther."},{"key":"B10","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1111\/imr.12621","article-title":"Overview of the IL-1 family in innate inflammation and acquired immunity.","volume":"281","author":"Dinarello","year":"2018","journal-title":"Immunol. Rev."},{"key":"B11","doi-asserted-by":"publisher","first-page":"12777","DOI":"10.1111\/jcmm.15869","article-title":"Long noncoding RNA TCONS-00106987 promotes atrial electrical remodelling during atrial fibrillation by sponging miR-26 to regulate KCNJ2.","volume":"24","author":"Du","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1007\/s11626-020-00459-0","article-title":"lncRNA-XIST protects the hypoxia-induced cardiomyocyte injury through regulating the miR-125b-hexokianse 2 axis.","volume":"56","author":"Fan","year":"2020","journal-title":"In Vitro Cell Dev. Biol. Anim."},{"key":"B13","doi-asserted-by":"crossref","DOI":"10.1186\/s13048-019-0508-2","article-title":"Identification of significant genes with poor prognosis in ovarian cancer via bioinformatical analysis.","volume":"12","author":"Feng","year":"2019","journal-title":"J. Ovarian. Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1007\/978-1-0716-0904-0_8","article-title":"Methylation in lung cancer: a brief review.","volume":"2204","author":"Gu","year":"2020","journal-title":"Methods Mol. Biol."},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.680918","article-title":"Hippo pathway core genes based prognostic signature and immune infiltration patterns in lung squamous cell carcinoma.","volume":"11","author":"Gu","year":"","journal-title":"Front. Oncol."},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2020.165921","article-title":"TEAD4 promotes tumor development in patients with lung adenocarcinoma via ERK signaling pathway.","volume":"1866","author":"Gu","year":"","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2020.627396","article-title":"Identification of common genes and pathways in eight fibrosis diseases.","volume":"11","author":"Gu","year":"","journal-title":"Front. Genet."},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbapap.2020.140444","article-title":"A comprehensive study of construction and analysis of competitive endogenous RNA networks in lung adenocarcinoma.","volume":"1868","author":"Gu","year":"","journal-title":"Biochim. Biophys. Acta Proteins Proteom."},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.661792","article-title":"Comprehensive analysis of the prognostic role and mutational characteristics of m6A-related genes in lung squamous cell carcinoma.","volume":"9","author":"Gu","year":"","journal-title":"Front. Cell Dev. Biol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1805","DOI":"10.1093\/bioinformatics\/bts251","article-title":"DAVID-WS: a stateful web service to facilitate gene\/protein list analysis.","volume":"28","author":"Jiao","year":"2012","journal-title":"Bioinformatics"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1027","DOI":"10.1111\/ene.12588","article-title":"Combined antithrombotic therapy of potential value in acute atrial fibrillation related stroke.","volume":"22","author":"Kelley","year":"2015","journal-title":"Eur. J. Neurol."},{"key":"B22","doi-asserted-by":"crossref","DOI":"10.1161\/CIRCEP.117.006040","article-title":"Interleukin 10 treatment ameliorates high-fat diet-induced inflammatory atrial remodeling and fibrillation.","volume":"11","author":"Kondo","year":"2018","journal-title":"Circ. Arrhythm Electrophysiol."},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0198461","article-title":"Circulating proteomic patterns in AF related left atrial remodeling indicate involvement of coagulation and complement cascade.","volume":"13","author":"Kornej","year":"2018","journal-title":"PLoS One"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-9-559","article-title":"WGCNA: an R package for weighted correlation network analysis.","volume":"9","author":"Langfelder","year":"2008","journal-title":"BMC Bioinformatics"},{"key":"B25","doi-asserted-by":"publisher","first-page":"114568","DOI":"10.18632\/oncotarget.21603","article-title":"LncRNA BANCR facilitates vascular smooth muscle cell proliferation and migration through JNK pathway.","volume":"8","author":"Li","year":"2017","journal-title":"Oncotarget"},{"key":"B26","first-page":"401","article-title":"Weighted gene coexpression network analysis to identify key modules and hub genes associated with atrial fibrillation.","volume":"45","author":"Li","year":"2020","journal-title":"Int. J. Mol. Med."},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2020.165906","article-title":"Identification of novel candidate genes in heterotaxy syndrome patients with congenital heart diseases by whole exome sequencing.","volume":"1866","author":"Liang","year":"2020","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"B28","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1016\/j.yjmcc.2018.09.007","article-title":"The role of immune cells in atrial fibrillation.","volume":"123","author":"Liu","year":"2018","journal-title":"J. Mol. Cell Cardiol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1713","DOI":"10.1093\/europace\/euq321","article-title":"Interleukin-18 among atrial fibrillation patients in the absence of structural heart disease.","volume":"12","author":"Luan","year":"2010","journal-title":"Europace"},{"key":"B30","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.hfc.2009.12.004","article-title":"Genetics of atrial fibrillation.","volume":"6","author":"Lubitz","year":"2010","journal-title":"Heart Fail Clin."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1939","DOI":"10.1172\/jci62185","article-title":"MicroRNA-26 governs profibrillatory inward-rectifier potassium current changes in atrial fibrillation.","volume":"123","author":"Luo","year":"2013","journal-title":"J. Clin. Invest."},{"key":"B32","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-020-77562-5","article-title":"Vascular endothelial growth factor promotes atrial arrhythmias by inducing acute intercalated disk remodeling.","volume":"10","author":"Mezache","year":"2020","journal-title":"Sci. Rep."},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1007\/s10840-021-00955-7","article-title":"Atrial fibrillation ablation: is common practice far from guidelines\u2019 world? The Italian experience from a national survey.","author":"Pelargonio","year":"2021","journal-title":"J. Interv. Card. Electrophysiol."},{"key":"B34","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.jacep.2015.04.010","article-title":"A systematic review on the progression of paroxysmal to persistent atrial fibrillation: shedding new light on the effects of catheter ablation.","volume":"1","author":"Proietti","year":"2015","journal-title":"JACC Clin. Electrophysiol."},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.7717\/peerj.11427","article-title":"Identification of diagnostic genes and vital microRNAs involved in rheumatoid arthritis: based on data mining and experimental verification.","volume":"9","author":"Ren","year":"2021","journal-title":"PeerJ"},{"key":"B36","doi-asserted-by":"publisher","first-page":"948","DOI":"10.1093\/europace\/eur418","article-title":"Increased intracardiac vascular endothelial growth factor levels in patients with paroxysmal, but not persistent atrial fibrillation.","volume":"14","author":"Scridon","year":"2012","journal-title":"Europace"},{"key":"B37","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/j.ebiom.2018.11.008","article-title":"Next-generation sequencing identifies novel genes with rare variants in total anomalous pulmonary venous connection.","volume":"38","author":"Shi","year":"2018","journal-title":"EBioMedicine"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2020.165757","article-title":"Genome-wide screening of functional long noncoding RNAs in the epicardial adipose tissues of atrial fibrillation.","volume":"1866","author":"Shi","year":"","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"B39","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1016\/j.csbj.2020.01.011","article-title":"Identification of rare variants in novel candidate genes in pulmonary atresia patients by next generation sequencing.","volume":"18","author":"Shi","year":"","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"B40","doi-asserted-by":"publisher","first-page":"135","DOI":"10.2174\/1871530315666150316121956","article-title":"VEGF-VEGFR system as a target for suppressing inflammation and other diseases.","volume":"15","author":"Shibuya","year":"2015","journal-title":"Endocr. Metab. Immune Disord. Drug Targets"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1","DOI":"10.2147\/vhrm.s49334","article-title":"Avoiding permanent atrial fibrillation: treatment approaches to prevent disease progression.","volume":"10","author":"Shukla","year":"2014","journal-title":"Vasc. Health Risk Manag."},{"key":"B42","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.amjcard.2015.10.022","article-title":"Diagnosing paroxysmal atrial fibrillation in patients with ischemic strokes and transient ischemic attacks using echocardiographic measurements of left atrium function.","volume":"117","author":"Skaarup","year":"2016","journal-title":"Am. J. Cardiol."},{"key":"B43","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/s41580-020-00315-9","article-title":"Gene regulation by long non-coding RNAs and its biological functions.","volume":"22","author":"Statello","year":"2021","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1160\/th16-07-0531","article-title":"The impact of CD4(+)CD28(null) T-lymphocytes on atrial fibrillation and mortality in patients with chronic heart failure.","volume":"117","author":"Sulzgruber","year":"2017","journal-title":"Thromb. Haemost."},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.tice.2020.101440","article-title":"Long non-coding RNA LICPAR regulates atrial fibrosis via TGF-beta\/Smad pathway in atrial fibrillation.","volume":"67","author":"Wang","year":"2020","journal-title":"Tissue Cell"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2019.109364","article-title":"LncRNA-LINC00472 contributes to the pathogenesis of atrial fibrillation (Af) by reducing expression of JP2 and RyR2 via miR-24.","volume":"120","author":"Wang","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"B47","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1016\/j.gene.2017.05.034","article-title":"Genetic variants of interleukin-18 are associated with reduced risk of atrial fibrillation in a population from Northeast China.","volume":"626","author":"Wang","year":"2017","journal-title":"Gene"},{"key":"B48","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1016\/j.devcel.2020.07.006","article-title":"Endogenous retrovirus-derived lncRNA BANCR promotes cardiomyocyte migration in humans and non-human primates.","volume":"54","author":"Wilson","year":"2020","journal-title":"Dev. Cell"},{"key":"B49","doi-asserted-by":"publisher","first-page":"2227","DOI":"10.1161\/circulationaha.118.035202","article-title":"Enhanced Cardiomyocyte NLRP3 inflammasome signaling promotes atrial fibrillation.","volume":"138","author":"Yao","year":"2018","journal-title":"Circulation"},{"key":"B50","doi-asserted-by":"publisher","first-page":"2605","DOI":"10.1007\/s11033-020-05347-0","article-title":"LncRNA MIAT\/miR-133a-3p axis regulates atrial fibrillation and atrial fibrillation-induced myocardial fibrosis.","volume":"47","author":"Yao","year":"2020","journal-title":"Mol. Biol. Rep."},{"key":"B51","doi-asserted-by":"crossref","DOI":"10.3892\/etm.2021.9908","article-title":"Long non-coding RNA XIST promotes the proliferation of cardiac fibroblasts and the accumulation of extracellular matrix by sponging microRNA-155-5p.","volume":"21","author":"Zhang","year":"2021","journal-title":"Exp. Ther. Med."},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2020.165917","article-title":"Identification of cell-to-cell interactions by ligand-receptor pairs in human fetal heart.","volume":"1866","author":"Zhang","year":"2020","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"B53","first-page":"1406","article-title":"[Clinical value of detecting serum soluble CD163 level in patients with atrial fibrillation].","volume":"36","author":"Zhong","year":"2016","journal-title":"Nan Fang Yi Ke Da Xue Xue Bao"},{"key":"B54","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.1159\/000490225","article-title":"Analysis of genes involved in persistent atrial fibrillation: comparisons of \u2018Trigger\u2019 and \u2018Substrate\u2019 Differences.","volume":"47","author":"Zou","year":"2018","journal-title":"Cell Physiol. Biochem."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.722671\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,4]],"date-time":"2021-10-04T05:42:47Z","timestamp":1633326167000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.722671\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,4]]},"references-count":54,"alternative-id":["10.3389\/fcell.2021.722671"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2021.722671","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,4]]},"article-number":"722671"}}