Disruption of NIPBL/Scc2 in Cornelia de Lange Syndrome provokes cohesin genome-wide redistribution with an impact in the transcriptome

Patricia Garcia (), Rita Fernandez-Hernandez, Ana Cuadrado, Ignacio Coca, Antonio Gomez, Maria Maqueda, Ana Latorre-Pellicer, Beatriz Puisac, Feliciano J. Ramos, Juan Sandoval, Manel Esteller, Jose Luis Mosquera, Jairo Rodriguez, J. Pié, Ana Losada and Ethel Queralt ()
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Patricia Garcia: Institut d’Investigacions Biomèdica de Bellvitge (IDIBELL), Av. Gran Via de L’Hospitalet 199-203
Rita Fernandez-Hernandez: Institut d’Investigacions Biomèdica de Bellvitge (IDIBELL), Av. Gran Via de L’Hospitalet 199-203
Ana Cuadrado: Spanish National Cancer Research Centre (CNIO)
Ignacio Coca: qGenomics Laboratory
Antonio Gomez: Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat
Maria Maqueda: Av. Gran Via de L’Hospitalet 199-203
Ana Latorre-Pellicer: University of Zaragoza, CIBERER-GCV02 and IISAragon
Beatriz Puisac: University of Zaragoza, CIBERER-GCV02 and IISAragon
Feliciano J. Ramos: University of Zaragoza, CIBERER-GCV02 and IISAragon
Juan Sandoval: Health Research Institute La Fe (IISLaFe)
Manel Esteller: Josep Carreras Leukaemia Research Institute (IJC)
Jose Luis Mosquera: Av. Gran Via de L’Hospitalet 199-203
Jairo Rodriguez: qGenomics Laboratory
J. Pié: University of Zaragoza, CIBERER-GCV02 and IISAragon
Ana Losada: Spanish National Cancer Research Centre (CNIO)
Ethel Queralt: Institut d’Investigacions Biomèdica de Bellvitge (IDIBELL), Av. Gran Via de L’Hospitalet 199-203

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Cornelia de Lange syndrome (CdLS) is a rare disease affecting multiple organs and systems during development. Mutations in the cohesin loader, NIPBL/Scc2, were first described and are the most frequent in clinically diagnosed CdLS patients. The molecular mechanisms driving CdLS phenotypes are not understood. In addition to its canonical role in sister chromatid cohesion, cohesin is implicated in the spatial organization of the genome. Here, we investigate the transcriptome of CdLS patient-derived primary fibroblasts and observe the downregulation of genes involved in development and system skeletal organization, providing a link to the developmental alterations and limb abnormalities characteristic of CdLS patients. Genome-wide distribution studies demonstrate a global reduction of NIPBL at the NIPBL-associated high GC content regions in CdLS-derived cells. In addition, cohesin accumulates at NIPBL-occupied sites at CpG islands potentially due to reduced cohesin translocation along chromosomes, and fewer cohesin peaks colocalize with CTCF.

Date: 2021
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DOI: 10.1038/s41467-021-24808-z

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