{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T05:38:08Z","timestamp":1770356288936,"version":"3.49.0"},"reference-count":27,"publisher":"The Company of Biologists","issue":"9","license":[{"start":{"date-parts":[[2020,9,5]],"date-time":"2020-09-05T00:00:00Z","timestamp":1599264000000},"content-version":"vor","delay-in-days":737,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0"}],"funder":[{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","award":["GGP14211"],"award-info":[{"award-number":["GGP14211"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001674","name":"Fondation Leducq","doi-asserted-by":"publisher","award":["TNE 15CVD01"],"award-info":[{"award-number":["TNE 15CVD01"]}],"id":[{"id":"10.13039\/501100001674","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministero dell'Istruzione, dell'Universit\u00e0 e della Ricerca\/FAREBIO"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,9,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>The TBX1 gene is haploinsufficient in 22q11.2 deletion syndrome (22q11.2DS), and genetic evidence from human patients and mouse models points to a major role of this gene in the pathogenesis of this syndrome. Tbx1 can activate and repress transcription, and previous work has shown that one of its functions is to negatively modulate cardiomyocyte differentiation. Tbx1 occupies the anterior heart field (AHF) enhancer of the Mef2c gene, which encodes a key cardiac differentiation transcription factor. Here, we show that increased dosage of Tbx1 correlates with downregulation of Mef2c expression and reduced acetylation of its AHF enhancer in cultured mouse myoblasts. Consistently, 22q11.2DS-derived and in vitro-differentiated human induced pluripotent stem cells (hiPSCs) expressed higher levels of MEF2C and showed increased AHF acetylation, compared with hiPSCs from a healthy donor. Most importantly, we show that in mouse embryos, loss of Tbx1 enhances the expression of the Mef2c-AHF-Cre transgene in a specific region of the splanchnic mesoderm, and in a dosage-dependent manner, providing an in vivo correlate of our cell culture data. These results indicate that Tbx1 regulates the Mef2c AHF enhancer by inducing histone deacetylation.<\/jats:p>","DOI":"10.1242\/dmm.029967","type":"journal-article","created":{"date-parts":[[2018,8,30]],"date-time":"2018-08-30T08:55:31Z","timestamp":1535619331000},"source":"Crossref","is-referenced-by-count":13,"title":["Tbx1 represses <i>Mef2c<\/i> gene expression and is correlated with histone 3 deacetylation of the anterior heart field enhancer"],"prefix":"10.1242","volume":"11","author":[{"given":"Luna Simona","family":"Pane","sequence":"first","affiliation":[{"name":"CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso 1 , Via Pietro Castellino 111, 80131 Napoli , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Filomena Gabriella","family":"Fulcoli","sequence":"additional","affiliation":[{"name":"CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso 1 , Via Pietro Castellino 111, 80131 Napoli , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Cirino","sequence":"additional","affiliation":[{"name":"University of Naples Federico II 2 Department of Molecular Medicine and Medical Biotechnology , , 80131 Napoli , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandra","family":"Altomonte","sequence":"additional","affiliation":[{"name":"CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso 1 , Via Pietro Castellino 111, 80131 Napoli , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosa","family":"Ferrentino","sequence":"additional","affiliation":[{"name":"CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso 1 , Via Pietro Castellino 111, 80131 Napoli , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marchesa","family":"Bilio","sequence":"additional","affiliation":[{"name":"CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso 1 , Via Pietro Castellino 111, 80131 Napoli , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5330-0256","authenticated-orcid":false,"given":"Antonio","family":"Baldini","sequence":"additional","affiliation":[{"name":"CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso 1 , Via Pietro Castellino 111, 80131 Napoli , Italy"},{"name":"University of Naples Federico II 2 Department of Molecular Medicine and Medical Biotechnology , , 80131 Napoli , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2018,8,30]]},"reference":[{"key":"2024061303503529400_DMM029967C1","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1016\/bs.ctdb.2016.08.002","article-title":"Tbx1: transcriptional and developmental functions","volume":"122","author":"Baldini","year":"2017","journal-title":"Curr. Top. Dev. Biol."},{"key":"2024061303503529400_DMM029967C2","doi-asserted-by":"publisher","first-page":"1410","DOI":"10.1093\/nar\/29.7.1410","article-title":"All Tcf HMG box transcription factors interact with Groucho-related co-repressors","volume":"29","author":"Brantjes","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"2024061303503529400_DMM029967C3","doi-asserted-by":"publisher","first-page":"842","DOI":"10.1161\/CIRCRESAHA.109.200295","article-title":"Tbx1 regulates proliferation and differentiation of multipotent heart progenitors","volume":"105","author":"Chen","year":"2009","journal-title":"Circ. Res."},{"key":"2024061303503529400_DMM029967C4","doi-asserted-by":"publisher","first-page":"e1002571","DOI":"10.1371\/journal.pgen.1002571","article-title":"Transcriptional control in cardiac progenitors: Tbx1 interacts with the BAF chromatin remodeling complex and regulates Wnt5a","volume":"8","author":"Chen","year":"2012","journal-title":"PLoS Genet."},{"key":"2024061303503529400_DMM029967C5","doi-asserted-by":"publisher","first-page":"3931","DOI":"10.1242\/dev.01256","article-title":"Mef2c is a direct transcriptional target of ISL1 and GATA factors in the anterior heart field during mouse embryonic development","volume":"131","author":"Dodou","year":"2004","journal-title":"Development"},{"key":"2024061303503529400_DMM029967C6","doi-asserted-by":"publisher","first-page":"25748","DOI":"10.1074\/jbc.M703724200","article-title":"Transcriptional repression by the T-box proteins Tbx18 and Tbx15 depends on Groucho corepressors","volume":"282","author":"Farin","year":"2007","journal-title":"J. Biol. Chem."},{"key":"2024061303503529400_DMM029967C7","doi-asserted-by":"publisher","first-page":"e6049","DOI":"10.1371\/journal.pone.0006049","article-title":"Tbx1 regulates the BMP-Smad1 pathway in a transcription independent manner","volume":"4","author":"Fulcoli","year":"2009","journal-title":"PLoS ONE"},{"key":"2024061303503529400_DMM029967C8","doi-asserted-by":"publisher","first-page":"11688","DOI":"10.1038\/ncomms11688","article-title":"Rebalancing gene haploinsufficiency in vivo by targeting chromatin","volume":"7","author":"Fulcoli","year":"2016","journal-title":"Nat. Commun."},{"key":"2024061303503529400_DMM029967C9","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.1242\/dev.071456","article-title":"RIPPLY3 is a retinoic acid-inducible repressor required for setting the borders of the pre-placodal ectoderm","volume":"139","author":"Janesick","year":"2012","journal-title":"Development"},{"key":"2024061303503529400_DMM029967C10","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1186\/gb-2008-9-1-205","article-title":"The Groucho\/TLE\/Grg family of transcriptional co-repressors","volume":"9","author":"Jennings","year":"2008","journal-title":"Genome Biol."},{"key":"2024061303503529400_DMM029967C11","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1038\/85845","article-title":"DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1","volume":"27","author":"Jerome","year":"2001","journal-title":"Nat. Genet."},{"key":"2024061303503529400_DMM029967C12","doi-asserted-by":"publisher","first-page":"5395","DOI":"10.1021\/pr400818c","article-title":"A Gro\/TLE-NuRD corepressor complex facilitates Tbx20-dependent transcriptional repression","volume":"12","author":"Kaltenbrun","year":"2013","journal-title":"J. Proteome Res."},{"key":"2024061303503529400_DMM029967C13","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1016\/S1534-5807(01)00040-5","article-title":"The arterial pole of the mouse heart forms from Fgf10-expressing cells in pharyngeal mesoderm","volume":"1","author":"Kelly","year":"2001","journal-title":"Dev. Cell"},{"key":"2024061303503529400_DMM029967C14","doi-asserted-by":"publisher","first-page":"1381","DOI":"10.1038\/nprot.2008.116","article-title":"Cardiac commitment of primate embryonic stem cells","volume":"3","author":"Leschik","year":"2008","journal-title":"Nat. Protoc."},{"key":"2024061303503529400_DMM029967C15","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1016\/j.ydbio.2008.01.037","article-title":"Identification of downstream genetic pathways of Tbx1 in the second heart field","volume":"316","author":"Liao","year":"2008","journal-title":"Dev. Biol."},{"key":"2024061303503529400_DMM029967C16","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1038\/35065105","article-title":"Tbx1 haploinsufficieny in the DiGeorge syndrome region causes aortic arch defects in mice","volume":"410","author":"Lindsay","year":"2001","journal-title":"Nature"},{"key":"2024061303503529400_DMM029967C17","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1016\/S0092-8674(01)00247-1","article-title":"TBX1 is responsible for cardiovascular defects in velo-cardio-facial\/digeorge syndrome","volume":"104","author":"Merscher","year":"2001","journal-title":"Cell"},{"key":"2024061303503529400_DMM029967C18","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1006\/dbio.2001.0409","article-title":"The outflow tract of the heart is recruited from a novel heart-forming field","volume":"238","author":"Mjaatvedt","year":"2001","journal-title":"Dev. Biol."},{"key":"2024061303503529400_DMM029967C19","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1096\/fj.09-139477","article-title":"Mouse and human induced pluripotent stem cells as a source for multipotent Isl1+ cardiovascular progenitors","volume":"24","author":"Moretti","year":"2010","journal-title":"FASEB J."},{"key":"2024061303503529400_DMM029967C20","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1242\/dev.054056","article-title":"Ripply3, a Tbx1 repressor, is required for development of the pharyngeal apparatus and its derivatives in mice","volume":"138","author":"Okubo","year":"2011","journal-title":"Development"},{"key":"2024061303503529400_DMM029967C21","doi-asserted-by":"publisher","first-page":"2485","DOI":"10.1093\/hmg\/dds063","article-title":"Tbx1 is a negative modulator of Mef2c","volume":"21","author":"Pane","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"2024061303503529400_DMM029967C22","doi-asserted-by":"publisher","first-page":"790","DOI":"10.1161\/CIRCRESAHA.115.305020","article-title":"Tbx1 coordinates addition of posterior second heart field progenitor cells to the arterial and venous poles of the heart","volume":"115","author":"Rana","year":"2014","journal-title":"Circ. Res."},{"key":"2024061303503529400_DMM029967C24","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1258\/ebm.2010.009318","article-title":"Ash2l interacts with Tbx1 and is required during early embryogenesis","volume":"235","author":"Stoller","year":"2010","journal-title":"Exp. Biol. Med. (Maywood)"},{"key":"2024061303503529400_DMM029967C25","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/j.ydbio.2005.08.041","article-title":"The right ventricle, outflow tract, and ventricular septum comprise a restricted expression domain within the secondary\/anterior heart field","volume":"287","author":"Verzi","year":"2005","journal-title":"Dev. Biol."},{"key":"2024061303503529400_DMM029967C26","doi-asserted-by":"crossref","first-page":"3179","DOI":"10.1242\/dev.128.16.3179","article-title":"Conotruncal myocardium arises from a secondary heart field","volume":"128","author":"Waldo","year":"2001","journal-title":"Development"},{"key":"2024061303503529400_DMM029967C27","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1016\/j.cell.2012.07.035","article-title":"Dynamic and coordinated epigenetic regulation of developmental transitions in the cardiac lineage","volume":"151","author":"Wamstad","year":"2012","journal-title":"Cell"},{"key":"2024061303503529400_DMM029967C28","doi-asserted-by":"publisher","first-page":"3217","DOI":"10.1242\/dev.01174","article-title":"Tbx1 has a dual role in the morphogenesis of the cardiac outflow tract","volume":"131","author":"Xu","year":"2004","journal-title":"Development"}],"container-title":["Disease Models &amp; Mechanisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1242\/dmm.029967","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.029967\/3486216\/dmm029967.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.029967\/3486216\/dmm029967.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,13]],"date-time":"2024-06-13T03:50:56Z","timestamp":1718250656000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dmm\/article\/11\/9\/dmm029967\/53596\/Tbx1-represses-Mef2c-gene-expression-and-is"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,8,30]]},"references-count":27,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2018,9,1]]}},"URL":"https:\/\/doi.org\/10.1242\/dmm.029967","relation":{},"ISSN":["1754-8411","1754-8403"],"issn-type":[{"value":"1754-8411","type":"electronic"},{"value":"1754-8403","type":"print"}],"subject":[],"published":{"date-parts":[[2018,8,30]]},"article-number":"dmm029967"}}