Transcriptional Dysregulation in NIPBL and Cohesin Mutant Human Cells

• Published in: PLoS biology Vol. 7; no. 5; p. e1000119
• Main Authors: Liu, Jinglan, Zhang, Zhe, Bando, Masashige, Itoh, Takehiko, Deardorff, Matthew A., Clark, Dinah, Kaur, Maninder, Tandy, Stephany, Kondoh, Tatsuro, Rappaport, Eric, Spinner, Nancy B., Vega, Hugo, Jackson, Laird G., Shirahige, Katsuhiko, Krantz, Ian D.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 26.05.2009; Public Library of Science (PLoS)
• Subjects: Analysis; Binding sites; Cell Biology/Gene Expression; Cell cycle; Cell Cycle Proteins - genetics; Chondroitin Sulfate Proteoglycans - genetics; Chromatin Immunoprecipitation; Chromosomal Proteins, Non-Histone - genetics; Databases, Genetic; De Lange Syndrome - genetics; Developmental Biology/Developmental Molecular Mechanisms; Developmental Biology/Molecular Development; Gene Expression Regulation; Genetic transcription; Genetics; Genetics and Genomics/Chromosome Biology; Genetics and Genomics/Epigenetics; Genetics and Genomics/Gene Expression; Genetics and Genomics/Genetics of Disease; Genetics and Genomics/Genomics; Genetics and Genomics/Medical Genetics; Genomes; Human cell culture; Oligonucleotide Array Sequence Analysis; Pediatrics and Child Health/Child Development; Polymerase Chain Reaction; Promoter Regions, Genetic - genetics; Proteins; Proteins - genetics; United States; Proteins; Promoter Regions, Genetic; Chromatin Immunoprecipitation; Oligonucleotide Array Sequence Analysis; Chromosomal Proteins, Non-Histone; Gene Expression Regulation; Polymerase Chain Reaction; Databases, Genetic; De Lange Syndrome; Cell Cycle Proteins; Chondroitin Sulfate Proteoglycans
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.1000119

Cohesin regulates sister chromatid cohesion during the mitotic cell cycle with Nipped-B-Like (NIPBL) facilitating its loading and unloading. In addition to this canonical role, cohesin has also been demonstrated to play a critical role in regulation of gene expression in nondividing cells. Heterozygous mutations in the cohesin regulator NIPBL or cohesin structural components SMC1A and SMC3 result in the multisystem developmental disorder Cornelia de Lange Syndrome (CdLS). Genome-wide assessment of transcription in 16 mutant cell lines from severely affected CdLS probands has identified a unique profile of dysregulated gene expression that was validated in an additional 101 samples and correlates with phenotypic severity. This profile could serve as a diagnostic and classification tool. Cohesin binding analysis demonstrates a preference for intergenic regions suggesting a cis-regulatory function mimicking that of a boundary/insulator interacting protein. However, the binding sites are enriched within the promoter regions of the dysregulated genes and are significantly decreased in CdLS proband, indicating an alternative role of cohesin as a transcription factor.