{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T18:02:45Z","timestamp":1784138565939,"version":"3.55.0"},"reference-count":80,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2021,11,29]],"date-time":"2021-11-29T00:00:00Z","timestamp":1638144000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100007368","name":"Fondazione Pisa","doi-asserted-by":"publisher","award":["120\/16"],"award-info":[{"award-number":["120\/16"]}],"id":[{"id":"10.13039\/100007368","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012264","name":"NIH","doi-asserted-by":"publisher","award":["X01 HL145697"],"award-info":[{"award-number":["X01 HL145697"]}],"id":[{"id":"10.13039\/501100012264","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000071","name":"NICHD","doi-asserted-by":"publisher","award":["R03 HD099530"],"award-info":[{"award-number":["R03 HD099530"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,5,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Cornelia de Lange syndrome (CdLS) is a rare multiorgan developmental disorder caused by pathogenic variants in cohesin genes. It is a genetically and clinically heterogeneous dominant (both autosomal and X-linked) rare disease. Increasing experimental evidence indicates that CdLS is caused by a combination of factors, such as gene expression dysregulation, accumulation of cellular damage and cellular aging, which collectively contribute to the CdLS phenotype. The CdLS phenotype overlaps with a number of related diagnoses such as KBG syndrome and Rubinstein\u2013Taybi syndrome both caused by variants in chromatin-associated factors other than cohesin. The molecular basis underlying these overlapping phenotypes is not clearly defined. Here, we found that cells from individuals with CdLS and CdLS-related diagnoses are characterized by global transcription disturbance and share common dysregulated pathways. Intriguingly, c-MYC (subsequently referred to as MYC) is downregulated in all cell lines and represents a convergent hub lying at the center of dysregulated pathways. Subsequent treatment with estradiol restores MYC expression by modulating cohesin occupancy at its promoter region. In addition, MYC activation leads to modification in expression in hundreds of genes, which in turn reduce the oxidative stress level and genome instability. Together, these results show that MYC plays a pivotal role in the etiopathogenesis of CdLS and CdLS-related diagnoses and represents a potential therapeutic target for these conditions.<\/jats:p>","DOI":"10.1093\/hmg\/ddab348","type":"journal-article","created":{"date-parts":[[2021,11,26]],"date-time":"2021-11-26T12:10:35Z","timestamp":1637928635000},"page":"1599-1609","source":"Crossref","is-referenced-by-count":9,"title":["Disease-associated <i>c-MYC<\/i> downregulation in human disorders of transcriptional regulation"],"prefix":"10.1093","volume":"31","author":[{"given":"Maria M","family":"Pallotta","sequence":"first","affiliation":[{"name":"Institute for Genetic and Biomedical Research (IRGB), National Research Council (CNR), 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maddalena","family":"Di Nardo","sequence":"additional","affiliation":[{"name":"Institute for Genetic and Biomedical Research (IRGB), National Research Council (CNR), 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"Sarogni","sequence":"additional","affiliation":[{"name":"Institute for Genetic and Biomedical Research (IRGB), National Research Council (CNR), 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian D","family":"Krantz","sequence":"additional","affiliation":[{"name":"Roberts Individualized Medical Genetics Center, Division of Human Genetics, The Department of Pediatrics, The Children's Hospital of Philadelphia, and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Musio","sequence":"additional","affiliation":[{"name":"Institute for Genetic and Biomedical Research (IRGB), National Research Council (CNR), 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,11,29]]},"reference":[{"key":"2022052023341514600_ref1","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1038\/s41576-018-0031-0","article-title":"Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement","volume":"19","author":"Kline","year":"2018","journal-title":"Nat. Rev. Genet."},{"key":"2022052023341514600_ref2","doi-asserted-by":"crossref","DOI":"10.1038\/ejhg.2014.270","article-title":"Clinical utility gene card for: Cornelia de Lange syndrome","volume":"23","author":"Ramos","year":"2015","journal-title":"Eur. J. Hum. Genet."},{"key":"2022052023341514600_ref3","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1136\/jmedgenet-2014-102573","article-title":"Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism","volume":"51","author":"Ansari","year":"2014","journal-title":"J. Med. Genet."},{"key":"2022052023341514600_ref4","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1086\/511888","article-title":"Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of cornelia de Lange syndrome with predominant mental retardation","volume":"80","author":"Deardorff","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"2022052023341514600_ref5","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1016\/j.ajhg.2012.04.019","article-title":"RAD21 mutations cause a human cohesinopathy","volume":"90","author":"Deardorff","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"2022052023341514600_ref6","doi-asserted-by":"crossref","first-page":"2888","DOI":"10.1093\/hmg\/ddu002","article-title":"Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large Fontanelle and X-linked inheritance","volume":"23","author":"Kaiser","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"2022052023341514600_ref7","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1038\/ng1364","article-title":"Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster nipped-B","volume":"36","author":"Krantz","year":"2004","journal-title":"Nat. Genet."},{"key":"2022052023341514600_ref8","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1038\/ng1779","article-title":"X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations","volume":"38","author":"Musio","year":"2006","journal-title":"Nat. Genet."},{"key":"2022052023341514600_ref9","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/s41588-018-0042-y","article-title":"BRD4 interacts with NIPBL and BRD4 is mutated in a Cornelia de Lange-like syndrome","volume":"50","author":"Olley","year":"2018","journal-title":"Nat. Genet."},{"key":"2022052023341514600_ref10","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1146\/annurev-genet-112618-043633","article-title":"Organization of Chromosomal DNA by SMC complexes","volume":"53","author":"Yatskevich","year":"2019","journal-title":"Annu. Rev. 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