title: Mutant cohesin affects RNA polymerase II regulation in Cornelia de Lange syndrome.
abstract: In addition to its role in sister chromatid cohesion, genome stability and integrity, the cohesin complex is involved in gene transcription. Mutations in core cohesin subunits SMC1A, SMC3 and RAD21, or their regulators NIPBL and HDAC8, cause Cornelia de Lange syndrome (CdLS). Recent evidence reveals that gene expression dysregulation could be the underlying mechanism for CdLS. These findings raise intriguing questions regarding the potential role of cohesin-mediated transcriptional control and pathogenesis. Here, we identified numerous dysregulated genes occupied by cohesin by combining the transcriptome of CdLS cell lines carrying mutations in SMC1A gene and ChIP-Seq data. Genome-wide analyses show that genes changing in expression are enriched for cohesin-binding. In addition, our results indicate that mutant cohesin impairs both RNA polymerase II (Pol II) transcription initiation at promoters and elongation in the gene body. These findings highlight the pivotal role of cohesin in transcriptional regulation and provide an explanation for the typical gene dysregulation observed in CdLS patients.
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Pisa, Italy.
authors.forename: Linda
authors.initials: L
authors.lastname: Mannini
authors.affiliation: Centre de recherche sur le cancer de l'Université Laval, Québec, Canada.|Centre de recherche du CHU de Québec (Hôtel-Dieu de Québec), Québec, Canada.
authors.forename: Fabien
authors.initials: F
authors.lastname: C Lamaze
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Pisa, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cucco
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Pisa, Italy.
authors.forename: Clelia
authors.initials: C
authors.lastname: Amato
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Pisa, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Quarantotti
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Pisa, Italy.
authors.forename: Ilaria M
authors.initials: IM
authors.lastname: Rizzo
authors.affiliation: Division of Human Genetics, The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Krantz
authors.affiliation: Centre de recherche sur le cancer de l'Université Laval, Québec, Canada.|Centre de recherche du CHU de Québec (Hôtel-Dieu de Québec), Québec, Canada.|Département de biologie moléculaire, biochimie médicale et pathologie, Faculté de Médecine, Université Laval, Québec, Canada.
authors.forename: Steve
authors.initials: S
authors.lastname: Bilodeau
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Pisa, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Musio
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics*; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D003635:De Lange Syndrome / Q000235:genetics*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015894:Genome, Human; D006801:Humans; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012319:RNA Polymerase II / Q000378:metabolism*; D014158:Transcription, Genetic; D000098550:Structural Maintenance of Chromosome Protein 1
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D000098550:Structural Maintenance of Chromosome Protein 1; D012319:RNA Polymerase II