{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T07:05:29Z","timestamp":1792047929720,"version":"4.4.0"},"reference-count":56,"publisher":"Rockefeller University Press","issue":"7","funder":[{"DOI":"10.13039\/100001003","name":"Boehringer Ingelheim","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001003","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["291740"],"award-info":[{"award-number":["291740"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004955","name":"Austrian Industrial Research Promotion Agency","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004955","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["WO 1972\/1-1"],"award-info":[{"award-number":["WO 1972\/1-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,6,27]]},"abstract":"<jats:p>E2A is an essential regulator of early B cell development. Here, we have demonstrated that E2A together with E2-2 controlled germinal center (GC) B cell and plasma cell development. As shown by the identification of regulated E2A,E2-2 target genes in activated B cells, these E-proteins directly activated genes with important functions in GC B cells and plasma cells by inducing and maintaining DNase I hypersensitive sites. Through binding to multiple enhancers in the Igh 3\u2032 regulatory region and Aicda locus, E-proteins regulated class switch recombination by inducing both Igh germline transcription and AID expression. By regulating 3\u2032 Igk and Igh enhancers and a distal element at the Prdm1 (Blimp1) locus, E-proteins contributed to Igk, Igh, and Prdm1 activation in plasmablasts. Together, these data identified E2A and E2-2 as central regulators of B cell immunity.<\/jats:p>","DOI":"10.1084\/jem.20152002","type":"journal-article","created":{"date-parts":[[2016,6,4]],"date-time":"2016-06-04T13:29:24Z","timestamp":1465046964000},"page":"1201-1221","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":119,"title":["Molecular functions of the transcription factors E2A and E2-2 in controlling germinal center B cell and plasma cell development"],"prefix":"10.1084","volume":"213","author":[{"given":"Miriam","family":"W\u00f6hner","sequence":"first","affiliation":[{"name":"Research Institute of Molecular Pathology, Vienna Biocenter, A-1030 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromi","family":"Tagoh","sequence":"additional","affiliation":[{"name":"Research Institute of Molecular Pathology, Vienna Biocenter, A-1030 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Bilic","sequence":"additional","affiliation":[{"name":"Research Institute of Molecular Pathology, Vienna Biocenter, A-1030 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Jaritz","sequence":"additional","affiliation":[{"name":"Research Institute of Molecular Pathology, Vienna Biocenter, A-1030 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela Kostanova","family":"Poliakova","sequence":"additional","affiliation":[{"name":"Research Institute of Molecular Pathology, Vienna Biocenter, A-1030 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Fischer","sequence":"additional","affiliation":[{"name":"Research Institute of Molecular Pathology, Vienna Biocenter, A-1030 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meinrad","family":"Busslinger","sequence":"additional","affiliation":[{"name":"Research Institute of Molecular Pathology, Vienna Biocenter, A-1030 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2016,6,3]]},"reference":[{"key":"2023072603235618800_bib1","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","article-title":"HTSeq--a Python framework to work with high-throughput sequencing data","volume":"31","author":"Anders","year":"2015","journal-title":"Bioinformatics."},{"key":"2023072603235618800_bib2","doi-asserted-by":"publisher","first-page":"3318","DOI":"10.1093\/bioinformatics\/bts607","article-title":"MULTOVL: fast multiple overlaps of genomic regions","volume":"28","author":"Asz\u00f3di","year":"2012","journal-title":"Bioinformatics."},{"key":"2023072603235618800_bib3","doi-asserted-by":"publisher","first-page":"3522","DOI":"10.1128\/MCB.13.6.3522","article-title":"E2A and E2-2 are subunits of B-cell-specific E2-box DNA-binding proteins","volume":"13","author":"Bain","year":"1993","journal-title":"Mol. Cell. Biol."},{"key":"2023072603235618800_bib4","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1016\/0092-8674(94)90077-9","article-title":"E2A proteins are required for proper B cell development and initiation of immunoglobulin gene rearrangements","volume":"79","author":"Bain","year":"1994","journal-title":"Cell."},{"key":"2023072603235618800_bib5","doi-asserted-by":"publisher","first-page":"55362","DOI":"10.1074\/jbc.M408654200","article-title":"E2A-PBX1 interacts directly with the KIX domain of CBP\/p300 in the induction of proliferation in primary hematopoietic cells","volume":"279","author":"Bayly","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2023072603235618800_bib6","doi-asserted-by":"publisher","first-page":"2857","DOI":"10.1002\/1521-4141(200010)30:10&lt;2857::AID-IMMU2857&gt;3.0.CO;2-G","article-title":"The basic helix-loop-helix transcription factor E2-2 is involved in T lymphocyte development","volume":"30","author":"Bergqvist","year":"2000","journal-title":"Eur. J. Immunol."},{"key":"2023072603235618800_bib7","doi-asserted-by":"publisher","first-page":"2370","DOI":"10.1074\/jbc.M211464200","article-title":"Regulation of E2A activities by histone acetyltransferases in B lymphocyte development","volume":"278","author":"Bradney","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2023072603235618800_bib8","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.1038\/nmeth.2688","article-title":"Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position","volume":"10","author":"Buenrostro","year":"2013","journal-title":"Nat. Methods."},{"key":"2023072603235618800_bib9","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1038\/nri1395","article-title":"Class-switch recombination: interplay of transcription, DNA deamination and DNA repair","volume":"4","author":"Chaudhuri","year":"2004","journal-title":"Nat. Rev. Immunol."},{"key":"2023072603235618800_bib10","doi-asserted-by":"publisher","first-page":"1596","DOI":"10.1101\/gad.216192.113","article-title":"A TAF4 coactivator function for E proteins that involves enhanced TFIID binding","volume":"27","author":"Chen","year":"2013","journal-title":"Genes Dev."},{"key":"2023072603235618800_bib11","doi-asserted-by":"publisher","first-page":"1145","DOI":"10.1084\/jem.20061952","article-title":"Regulation of AID expression in the immune response","volume":"204","author":"Crouch","year":"2007","journal-title":"J. Exp. Med."},{"key":"2023072603235618800_bib12","doi-asserted-by":"publisher","first-page":"D662","DOI":"10.1093\/nar\/gku1010","article-title":"Ensembl 2015","volume":"43","author":"Cunningham","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"2023072603235618800_bib13","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1016\/j.immuni.2006.01.012","article-title":"Gene repression by Pax5 in B cells is essential for blood cell homeostasis and is reversed in plasma cells","volume":"24","author":"Delogu","year":"2006","journal-title":"Immunity."},{"key":"2023072603235618800_bib14","doi-asserted-by":"publisher","first-page":"1722","DOI":"10.1038\/nprot.2007.243","article-title":"Quantitative analysis of chromosome conformation capture assays (3C-qPCR)","volume":"2","author":"Hag\u00e8ge","year":"2007","journal-title":"Nat. Protoc."},{"key":"2023072603235618800_bib15","doi-asserted-by":"publisher","first-page":"3887","DOI":"10.1093\/emboj\/cdg380","article-title":"Myeloid lineage switch of Pax5 mutant but not wild-type B cell progenitors by C\/EBPalpha and GATA factors","volume":"22","author":"Heavey","year":"2003","journal-title":"EMBO J."},{"key":"2023072603235618800_bib16","doi-asserted-by":"publisher","first-page":"e61433","DOI":"10.1371\/journal.pone.0061433","article-title":"In vivo analysis of Aicda gene regulation: a critical balance between upstream enhancers and intronic silencers governs appropriate expression","volume":"8","author":"Huong","year":"2013","journal-title":"PLoS One."},{"key":"2023072603235618800_bib17","doi-asserted-by":"publisher","first-page":"1205","DOI":"10.1084\/jem.20041135","article-title":"Important roles for E protein binding sites within the immunoglobulin \u03ba chain intronic enhancer in activating Vkappa Jkappa rearrangement","volume":"200","author":"Inlay","year":"2004","journal-title":"J. Exp. Med."},{"key":"2023072603235618800_bib18","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1016\/j.immuni.2012.02.010","article-title":"E protein transcription factors are required for the development of CD4+ lineage T cells","volume":"36","author":"Jones-Mason","year":"2012","journal-title":"Immunity."},{"key":"2023072603235618800_bib19","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1084\/jem.20040973","article-title":"Plasma cell ontogeny defined by quantitative changes in blimp-1 expression","volume":"200","author":"Kallies","year":"2004","journal-title":"J. Exp. Med."},{"key":"2023072603235618800_bib20","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1016\/j.immuni.2007.04.007","article-title":"Initiation of plasma-cell differentiation is independent of the transcription factor Blimp-1","volume":"26","author":"Kallies","year":"2007","journal-title":"Immunity."},{"key":"2023072603235618800_bib21","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1038\/nri2507","article-title":"E and ID proteins branch out","volume":"9","author":"Kee","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"2023072603235618800_bib22","doi-asserted-by":"publisher","first-page":"1507","DOI":"10.1016\/j.cell.2013.11.039","article-title":"Interactome maps of mouse gene regulatory domains reveal basic principles of transcriptional regulation","volume":"155","author":"Kieffer-Kwon","year":"2013","journal-title":"Cell."},{"key":"2023072603235618800_bib23","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1016\/j.ymeth.2012.06.019","article-title":"SATB1-mediated functional packaging of chromatin into loops","volume":"58","author":"Kohwi-Shigematsu","year":"2012","journal-title":"Methods."},{"key":"2023072603235618800_bib24","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1016\/j.immuni.2008.04.014","article-title":"Instructive role of the transcription factor E2A in early B lymphopoiesis and germinal center B cell development","volume":"28","author":"Kwon","year":"2008","journal-title":"Immunity."},{"key":"2023072603235618800_bib25","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"2023072603235618800_bib26","doi-asserted-by":"publisher","first-page":"1696","DOI":"10.1093\/bioinformatics\/btr189","article-title":"MEME-ChIP: motif analysis of large DNA datasets","volume":"27","author":"Machanick","year":"2011","journal-title":"Bioinformatics."},{"key":"2023072603235618800_bib27","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1146\/annurev.immunol.26.021607.090241","article-title":"Regulation and functions of Blimp-1 in T and B lymphocytes","volume":"26","author":"Martins","year":"2008","journal-title":"Annu. Rev. Immunol."},{"key":"2023072603235618800_bib28","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/j.immuni.2013.08.011","article-title":"Flexible long-range loops in the VH gene region of the Igh locus facilitate the generation of a diverse antibody repertoire","volume":"39","author":"Medvedovic","year":"2013","journal-title":"Immunity."},{"key":"2023072603235618800_bib29","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1038\/ni.3349","article-title":"Multifunctional role of the transcription factor Blimp-1 in coordinating plasma cell differentiation","volume":"17","author":"Minnich","year":"2016","journal-title":"Nat. Immunol."},{"key":"2023072603235618800_bib30","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1016\/S0092-8674(00)00078-7","article-title":"Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme","volume":"102","author":"Muramatsu","year":"2000","journal-title":"Cell."},{"key":"2023072603235618800_bib31","doi-asserted-by":"publisher","first-page":"1079","DOI":"10.1038\/ni1260","article-title":"Helix-loop-helix proteins and lymphocyte development","volume":"6","author":"Murre","year":"2005","journal-title":"Nat. Immunol."},{"key":"2023072603235618800_bib32","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1016\/0092-8674(89)90682-X","article-title":"A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins","volume":"56","author":"Murre","year":"1989","journal-title":"Cell."},{"key":"2023072603235618800_bib33","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1038\/ncomms1475","article-title":"In-vitro derived germinal centre B cells differentially generate memory B or plasma cells in vivo.","volume":"2","author":"Nojima","year":"2011","journal-title":"Nat. Commun."},{"key":"2023072603235618800_bib34","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.immuni.2008.05.009","article-title":"Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages","volume":"29","author":"Nurieva","year":"2008","journal-title":"Immunity."},{"key":"2023072603235618800_bib35","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1038\/nri3795","article-title":"The generation of antibody-secreting plasma cells","volume":"15","author":"Nutt","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"2023072603235618800_bib36","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1038\/nature03813","article-title":"Blimp1 is a critical determinant of the germ cell lineage in mice","volume":"436","author":"Ohinata","year":"2005","journal-title":"Nature."},{"key":"2023072603235618800_bib37","doi-asserted-by":"publisher","first-page":"5066","DOI":"10.1093\/emboj\/17.17.5066","article-title":"OCA-B integrates B cell antigen receptor-, CD40L- and IL 4-mediated signals for the germinal center pathway of B cell development","volume":"17","author":"Qin","year":"1998","journal-title":"EMBO J."},{"key":"2023072603235618800_bib38","doi-asserted-by":"publisher","first-page":"6307","DOI":"10.1093\/emboj\/18.22.6307","article-title":"E2A activity is induced during B-cell activation to promote immunoglobulin class switch recombination","volume":"18","author":"Quong","year":"1999","journal-title":"EMBO J."},{"key":"2023072603235618800_bib39","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1038\/35085509","article-title":"Plasma cell differentiation requires the transcription factor XBP-1","volume":"412","author":"Reimold","year":"2001","journal-title":"Nature."},{"key":"2023072603235618800_bib40","doi-asserted-by":"publisher","first-page":"3130","DOI":"10.1038\/emboj.2012.155","article-title":"The B-cell identity factor Pax5 regulates distinct transcriptional programmes in early and late B lymphopoiesis","volume":"31","author":"Revilla-i-Domingo","year":"2012","journal-title":"EMBO J."},{"key":"2023072603235618800_bib41","doi-asserted-by":"publisher","first-page":"7084","DOI":"10.1038\/ncomms8084","article-title":"Elucidation of IgH 3\u2032 region regulatory role during class switch recombination via germline deletion","volume":"6","author":"Saintamand","year":"2015","journal-title":"Nat. Commun."},{"key":"2023072603235618800_bib42","doi-asserted-by":"publisher","first-page":"586","DOI":"10.1038\/ni923","article-title":"E-proteins directly regulate expression of activation-induced deaminase in mature B cells","volume":"4","author":"Sayegh","year":"2003","journal-title":"Nat. Immunol."},{"key":"2023072603235618800_bib43","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.immuni.2007.05.019","article-title":"Transcription factor Pax5 activates the chromatin of key genes involved in B cell signaling, adhesion, migration, and immune function","volume":"27","author":"Schebesta","year":"2007","journal-title":"Immunity."},{"key":"2023072603235618800_bib44","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1038\/383538a0","article-title":"B-cell-specific coactivator OBF-1\/OCA-B\/Bob1 required for immune response and germinal centre formation","volume":"383","author":"Schubart","year":"1996","journal-title":"Nature."},{"key":"2023072603235618800_bib45","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1016\/S1074-7613(03)00267-X","article-title":"Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory B cells","volume":"19","author":"Shapiro-Shelef","year":"2003","journal-title":"Immunity."},{"key":"2023072603235618800_bib46","doi-asserted-by":"publisher","first-page":"4518","DOI":"10.1128\/MCB.15.8.4518","article-title":"B-cell-specific DNA binding by an E47 homodimer","volume":"15","author":"Shen","year":"1995","journal-title":"Mol. Cell. Biol."},{"key":"2023072603235618800_bib47","doi-asserted-by":"publisher","first-page":"2996","DOI":"10.1093\/emboj\/16.11.2996","article-title":"The extent of affinity maturation differs between the memory and antibody-forming cell compartments in the primary immune response","volume":"16","author":"Smith","year":"1997","journal-title":"EMBO J."},{"key":"2023072603235618800_bib48","doi-asserted-by":"publisher","first-page":"2349","DOI":"10.1101\/gad.399506","article-title":"CTCF mediates long-range chromatin looping and local histone modification in the \u03b2-globin locus","volume":"20","author":"Splinter","year":"2006","journal-title":"Genes Dev."},{"key":"2023072603235618800_bib49","doi-asserted-by":"publisher","first-page":"3328","DOI":"10.4049\/jimmunol.1201042","article-title":"High rate of antibody secretion is not integral to plasma cell differentiation as revealed by XBP-1 deficiency","volume":"189","author":"Taubenheim","year":"2012","journal-title":"J. Immunol."},{"key":"2023072603235618800_bib50","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1093\/bioinformatics\/btp120","article-title":"TopHat: discovering splice junctions with RNA-Seq","volume":"25","author":"Trapnell","year":"2009","journal-title":"Bioinformatics."},{"key":"2023072603235618800_bib51","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1146\/annurev-immunol-020711-075032","article-title":"Germinal centers","volume":"30","author":"Victora","year":"2012","journal-title":"Annu. Rev. Immunol."},{"key":"2023072603235618800_bib52","doi-asserted-by":"publisher","first-page":"1895","DOI":"10.1182\/blood-2010-01-264689","article-title":"Genomic deletion of the whole IgH 3\u2032 regulatory region (hs3a, hs1,2, hs3b, and hs4) dramatically affects class switch recombination and Ig secretion to all isotypes","volume":"116","author":"Vincent-Fabert","year":"2010","journal-title":"Blood."},{"key":"2023072603235618800_bib53","doi-asserted-by":"publisher","first-page":"1370","DOI":"10.1016\/j.cell.2013.08.022","article-title":"One-step generation of mice carrying reporter and conditional alleles by CRISPR\/Cas-mediated genome engineering","volume":"154","author":"Yang","year":"2013","journal-title":"Cell."},{"key":"2023072603235618800_bib54","doi-asserted-by":"publisher","first-page":"1084","DOI":"10.1038\/ni.2688","article-title":"MEF2B mutations lead to deregulated expression of the oncogene BCL6 in diffuse large B cell lymphoma","volume":"14","author":"Ying","year":"2013","journal-title":"Nat. Immunol."},{"key":"2023072603235618800_bib55","doi-asserted-by":"publisher","first-page":"R137","DOI":"10.1186\/gb-2008-9-9-r137","article-title":"Model-based analysis of ChIP-Seq (MACS)","volume":"9","author":"Zhang","year":"2008","journal-title":"Genome Biol."},{"key":"2023072603235618800_bib56","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1016\/0092-8674(94)90076-0","article-title":"The helix-loop-helix gene E2A is required for B cell formation","volume":"79","author":"Zhuang","year":"1994","journal-title":"Cell."}],"container-title":["Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/213\/7\/1201\/1755338\/jem_20152002.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/213\/7\/1201\/1755338\/jem_20152002.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T23:25:01Z","timestamp":1690327501000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/213\/7\/1201\/42189\/Molecular-functions-of-the-transcription-factors"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,6,3]]},"references-count":56,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2016,6,27]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20152002","relation":{},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,6,3]]}}}