{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T00:04:16Z","timestamp":1788566656044,"version":"build-2803163510"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T00:00:00Z","timestamp":1667520000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005046","name":"Natural Science Foundation of Heilongjiang Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005046","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Vet. Sci."],"abstract":"<jats:p>The present study aimed to search for functional mutations within the promoter of porcine<jats:italic>STAT3<\/jats:italic>and to provide causative genetic variants associated with piglet diarrhea. We firstly confirmed that<jats:italic>STAT3<\/jats:italic>expressed higher in the small intestine than in the spleen, stomach and large intestine of SPF piglets, respectively (<jats:italic>P<\/jats:italic>&amp;lt; 0.05). Then, 10 genetic variations in the porcine STAT3 promoter region was identified by direct sequencing. Among them, three mutations SNP1: g.\u2212870 G&amp;gt;A, SNP2: g.\u2212584 A&amp;gt;C and a 6-bp Indel in the promoter region that displayed significant differential transcriptional activities were identified. Association analyses showed that SNP1: g.\u2212870 G&amp;gt;A was significantly associated with piglet diarrhea (<jats:italic>P<\/jats:italic>&amp;lt; 0.05) and the GG animals had lower diarrhea score than AA piglets (<jats:italic>P<\/jats:italic>&amp;lt; 0.01) in both Min and Landrace population. Further functional analysis revealed that E2F6 repressed the transcriptional efficiency of<jats:italic>STAT3 in vitro<\/jats:italic>, by binding the G allele of SNP1. The present study suggested that SNP1: g.\u2212870 G&amp;gt;A was a piglet diarrhea-associated variant that directly affected binding with E2F6, leading to changes in<jats:italic>STAT3<\/jats:italic>transcription which might partially contribute to piglet diarrhea susceptibility or resistance.<\/jats:p>","DOI":"10.3389\/fvets.2022.1034187","type":"journal-article","created":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T05:35:02Z","timestamp":1667540102000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["A functional mutation associated with piglet diarrhea partially by regulating the transcription of porcine STAT3"],"prefix":"10.3389","volume":"9","author":[{"given":"Zhihua","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diwen","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongchun","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingxing","family":"Kou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuqin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengwei","family":"Di","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiancheng","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xibiao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Buyue","family":"Niu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"11495","DOI":"10.1073\/pnas.1806068115","article-title":"Global trends in infectious diseases of swine","volume":"115","author":"VanderWaal","year":"2018","journal-title":"Proc Natl Acad Sci U S A."},{"key":"B2","doi-asserted-by":"publisher","first-page":"100286","DOI":"10.1016\/j.animal.2021.100286","article-title":"Review: livestock disease resilience: from individual to herd level","volume":"23","author":"Doeschl-Wilson","year":"2021","journal-title":"Animal."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1420","DOI":"10.3389\/fmicb.2020.01420","article-title":"Analysis of genetic variation in the bovine SLC11A1 gene, its influence on the expression of NRAMP1 and potential association with resistance to bovine tuberculosis","volume":"11","author":"Holder","year":"2020","journal-title":"Front Microbiol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"9362","DOI":"10.1073\/pnas.0903103106","article-title":"Potential etiologic and functional implications of genome-wide association loci for human diseases and traits","volume":"106","author":"Hindorff","year":"2009","journal-title":"Proc Natl Acad Sci U S A."},{"key":"B5","doi-asserted-by":"publisher","first-page":"5848","DOI":"10.1038\/s41467-021-26153-7","article-title":"Pig genome functional annotation enhances the biological interpretation of complex traits and human disease","volume":"12","author":"Pan","year":"2021","journal-title":"Nat Commun."},{"key":"B6","doi-asserted-by":"publisher","first-page":"11257","DOI":"10.1096\/fj.202000477R","article-title":"Two coupled mutations abolished the binding of CEBPB to the promoter of CXCL14 that displayed an antiviral effect on PRRSV by activating IFN signaling","volume":"34","author":"Niu","year":"2020","journal-title":"FASEB J."},{"key":"B7","doi-asserted-by":"publisher","first-page":"110202","DOI":"10.1016\/j.vetimm.2021.110202","article-title":"A 14 bp indel polymorphism in the promoter region is associated with different responses to porcine circovirus type 2 infection by regulating MRC1 transcription","volume":"234","author":"Liu","year":"2021","journal-title":"Vet Immunol Immunopathol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1146\/annurev-med-051113-024537","article-title":"The JAK-STAT pathway: impact on human disease and therapeutic intervention","volume":"66","author":"O'Shea","year":"2015","journal-title":"Annu Rev Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"21","DOI":"10.4049\/jimmunol.1401867","article-title":"Mechanisms of Jak\/STAT signaling in immunity and disease","volume":"194","author":"Villarino","year":"2015","journal-title":"J Immunol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1038\/nrclinonc.2018.8","article-title":"Targeting the IL-6\/JAK\/STAT3 signalling axis in cancer","volume":"15","author":"Johnson","year":"2018","journal-title":"Nat Rev Clin Oncol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"2449","DOI":"10.1128\/JVI.01769-06","article-title":"Persistent activation of STAT3 by latent Kaposi's sarcoma-associated herpesvirus infection of endothelial cells","volume":"81","author":"Punjabi","year":"2007","journal-title":"J Virol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1073\/pnas.1114232109","article-title":"Signal transducer and activator of transcription 3 (STAT3) and survivin induction by varicella-zoster virus promote replication and skin pathogenesis","volume":"109","author":"Sen","year":"2012","journal-title":"Proc Natl Acad Sci U S A."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1058","DOI":"10.1038\/nature06096","article-title":"Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome","volume":"448","author":"Minegishi","year":"2007","journal-title":"Nature."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1608","DOI":"10.1056\/NEJMoa073687","article-title":"STAT3 mutations in the hyper-IgE syndrome","volume":"357","author":"Holland","year":"2007","journal-title":"N Engl J Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.coi.2014.01.015","article-title":"STAT3 is a central regulator of lymphocyte differentiation and function","volume":"28","author":"Kane","year":"2014","journal-title":"Curr Opin Immunol."},{"key":"B16","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1038\/nature11582","article-title":"Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease","volume":"491","author":"Jostins","year":"2012","journal-title":"Nature."},{"key":"B17","doi-asserted-by":"publisher","first-page":"3325","DOI":"10.4049\/jimmunol.1900031","article-title":"STAT3 and STAT5 signaling thresholds determine distinct regulation for innate receptor-induced inflammatory cytokines, and STAT3\/STAT5 disease variants modulate these outcomes","volume":"203","author":"Hedl","year":"2019","journal-title":"J Immunol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"55","DOI":"10.4149\/av_2016_01_55","article-title":"The rate of co-infection for piglet diarrhea viruses in China and the genetic characterization of porcine epidemic diarrheavirus and porcine kobuvirus","volume":"60","author":"Zhao","year":"2016","journal-title":"Acta Virol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"572425","DOI":"10.3389\/fvets.2020.572425","article-title":"The roles of apoptosis in swine response to viral infection and pathogenesis of swine enteropathogenic coronaviruses","volume":"7","author":"Xu","year":"2020","journal-title":"Front Vet Sci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"e02095","DOI":"10.1128\/JVI.02095-17","article-title":"Porcine epidemic diarrhea virus-induced epidermal growth factor receptor activation impairs the antiviral activity of type I interferon","volume":"92","author":"Yang","year":"2018","journal-title":"J Virol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1186\/s12864-020-07306-2","article-title":"Transcriptome analysis reveals modulation of the STAT family in PEDV-infected IPEC-J2 cells","volume":"21","author":"Hu","year":"2020","journal-title":"BMC Genomics."},{"key":"B22","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/j.intimp.2016.04.032","article-title":"Developmental expression of STATs, nuclear factor-\u03baB and inflammatory genes in the jejunum of piglets during weaning","volume":"36","author":"Yi","year":"2016","journal-title":"Int Immunopharmacol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"e105013","DOI":"10.1371\/journal.pone.0105013","article-title":"Refined candidate region for F4ab\/ac enterotoxigenic Escherichia coli susceptibility situated proximal to MUC13 in pigs","volume":"9","author":"Goetstouwers","year":"2014","journal-title":"PLoS ONE."},{"key":"B24","doi-asserted-by":"publisher","first-page":"e0202970","DOI":"10.1371\/journal.pone.0202970","article-title":"Effects of alpha (1-2) fucosyltransferase genotype variants on plasma metabolome, immune responses and gastrointestinal bacterial enumeration of pigs pre- and post-weaning","volume":"13","author":"Riis Poulsen","year":"2018","journal-title":"PLoS ONE."},{"key":"B25","doi-asserted-by":"publisher","first-page":"79","DOI":"10.19720\/j.cnki.issn.1005-9369.2014.09.012","article-title":"Variations between breeds of suckling piglets in diarrhea occurrence time and degree and effect on weight gain","volume":"45","author":"Wang","year":"2014","journal-title":"J Northeast Agric Univ."},{"key":"B26","doi-asserted-by":"crossref","first-page":"333","DOI":"10.2460\/ajvr.1994.55.03.333","article-title":"Resistance of Chinese Meishan, Fengjing, and min pigs to the K88ac+ strain of Escherichia coli","volume":"55","author":"Michaels","year":"1994","journal-title":"Am J Vet Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"131","DOI":"10.13881\/j.cnki.hljxmsy.2021.07.0028","article-title":"Genetic base analysis of conservation population of min pigs","author":"Zhang","year":"2022","journal-title":"Heilongjiang Anim Sci Vet Med."},{"key":"B28","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1016\/S0034-5288(18)31082-8","article-title":"Effect of creep feeding on the incidence, duration, and severity of post-weaning diarrhea in pigs","volume":"49","author":"Kelly","year":"1990","journal-title":"Res Vet Sci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods."},{"key":"B30","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.antiviral.2017.03.006","article-title":"IL-22 suppresses the infection of porcine enteric coronaviruses and rotavirus by activating STAT3 signal pathway","volume":"142","author":"Xue","year":"2017","journal-title":"Antiviral Res."},{"key":"B31","doi-asserted-by":"publisher","first-page":"2287","DOI":"10.1021\/acs.jafc.7b00324","article-title":"AMPK\/\u03b1-ketoglutarate axis regulates intestinal water and ion homeostasis in young pigs","volume":"65","author":"He","year":"2017","journal-title":"J Agric Food Chem."},{"key":"B32","doi-asserted-by":"publisher","first-page":"skab065","DOI":"10.1093\/jas\/skab065","article-title":"Weaning causes a prolonged but transient change in immune gene expression in the intestine of piglets","volume":"99","author":"De Groot","year":"2021","journal-title":"J Anim Sci"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1190","DOI":"10.1126\/science.1222794","article-title":"Systematic localization of common disease-associated variation in regulatory DNA","volume":"337","author":"Maurano","year":"2012","journal-title":"Science."},{"key":"B34","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1038\/nrg3891","article-title":"The role of regulatory variation in complex traits and disease","volume":"16","author":"Albert","year":"2015","journal-title":"Nat Rev Genet."},{"key":"B35","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/s13073-018-0513-x","article-title":"An integrative functional genomics framework for effective identification of novel regulatory variants in genome-phenome studies","volume":"10","author":"Zhao","year":"2018","journal-title":"Genome Med."},{"key":"B36","doi-asserted-by":"publisher","first-page":"4665","DOI":"10.4049\/jimmunol.1300581","article-title":"Identification of a tissue-specific, C\/EBP\u03b2-dependent pathway of differentiation for murine peritoneal macrophages","volume":"191","author":"Cain","year":"2013","journal-title":"J Immunol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1016\/j.bbi.2019.05.034","article-title":"C\/EBP\u03b2 regulates the M2 transcriptome in \u03b2-adrenergic-stimulated macrophages","volume":"80","author":"Lamkin","year":"2019","journal-title":"Brain Behav Immun."},{"key":"B38","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1038\/37507","article-title":"An E2F-like repressor of transcription","volume":"390","author":"Morkel","year":"1997","journal-title":"Nature."},{"key":"B39","doi-asserted-by":"publisher","first-page":"2850","DOI":"10.1073\/pnas.95.6.2850","article-title":"E2F-6, a member of the E2F family that can behave as a transcriptional repressor","volume":"95","author":"Trimarchi","year":"1998","journal-title":"Proc Natl Acad Sci U S A."},{"key":"B40","doi-asserted-by":"publisher","first-page":"2941","DOI":"10.1101\/gad.1239304","article-title":"A role for E2F6 in distinguishing G1\/S- and G2\/M-specific transcription","volume":"18","author":"Giangrande","year":"2004","journal-title":"Genes Dev."},{"key":"B41","doi-asserted-by":"publisher","first-page":"2939","DOI":"10.1038\/s41467-019-10901-x","article-title":"E2F4 regulates transcriptional activation in mouse embryonic stem cells independently of the RB family","volume":"10","author":"Hsu","year":"2019","journal-title":"Nat Commun."},{"key":"B42","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1002\/cbin.11225","article-title":"Transcription factor E2F4 is a positive regulator of milk biosynthesis and proliferation of bovine mammary epithelial cells","volume":"44","author":"Zhen","year":"2019","journal-title":"Cell Biol Int"},{"key":"B43","doi-asserted-by":"publisher","first-page":"65","DOI":"10.7150\/ijbs.62106","article-title":"Cellular Id1 inhibits hepatitis B virus transcription by interacting with the novel covalently closed circular DNA-binding protein E2F4","volume":"18","author":"Wei","year":"2022","journal-title":"Int J Biol Sci."},{"key":"B44","doi-asserted-by":"publisher","first-page":"3183","DOI":"10.1080\/15384101.2016.1234551","article-title":"Novel functions for the transcription factor E2F4 in development and disease","volume":"15","author":"Hsu","year":"2016","journal-title":"Cell Cycle."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1519","DOI":"10.1073\/pnas.98.4.1519","article-title":"The E2F6 transcription factor is a component of the mammalian Bmi1-containing polycomb complex","volume":"98","author":"Trimarchi","year":"2001","journal-title":"Proc Natl Acad Sci U S A."},{"key":"B46","doi-asserted-by":"publisher","first-page":"8695","DOI":"10.1128\/JVI.00579-08","article-title":"Human papillomavirus type 16 E7 oncoprotein associates with E2F6","volume":"82","author":"McLaughlin-Drubin","year":"2008","journal-title":"J Virol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"4535","DOI":"10.1021\/acs.jafc.9b00007","article-title":"Promoter methylation regulates ApoA-I gene transcription in chicken abdominal adipose tissue","volume":"67","author":"Wu","year":"2019","journal-title":"J Agric Food Chem."},{"key":"B48","doi-asserted-by":"publisher","first-page":"e1000162","DOI":"10.1371\/journal.pgen.1000162","article-title":"An Sp1\/Sp3 binding polymorphism confers methylation protection","volume":"4","author":"Boumber","year":"2008","journal-title":"PLoS Genet."},{"key":"B49","doi-asserted-by":"publisher","first-page":"e04094","DOI":"10.7554\/eLife.04094","article-title":"High-throughput engineering of a mammalian genome reveals building principles of methylation states at CG rich regions","volume":"3","author":"Krebs","year":"2014","journal-title":"Elife."},{"key":"B50","doi-asserted-by":"publisher","first-page":"3582","DOI":"10.1038\/s41467-021-23596-w","article-title":"E2F6 initiates stable epigenetic silencing of germline genes during embryonic development","volume":"12","author":"Dahlet","year":"2021","journal-title":"Nat Commun."},{"key":"B51","doi-asserted-by":"publisher","first-page":"7020","DOI":"10.1038\/s41467-021-27345-x","article-title":"Repression of germline genes by PRC16 and SETDB1 in the early embryo precedes DNA methylation-mediated silencing","volume":"12","author":"Mochizuki","year":"2021","journal-title":"Nat Commun."}],"container-title":["Frontiers in Veterinary Science"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fvets.2022.1034187\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,7]],"date-time":"2024-10-07T06:44:33Z","timestamp":1728283473000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fvets.2022.1034187\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,4]]},"references-count":51,"alternative-id":["10.3389\/fvets.2022.1034187"],"URL":"https:\/\/doi.org\/10.3389\/fvets.2022.1034187","relation":{},"ISSN":["2297-1769"],"issn-type":[{"value":"2297-1769","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,4]]},"article-number":"1034187"}}