Disruption of NIPBL/Scc2 in Cornelia de Lange Syndrome provokes cohesin genome-wide redistribution with an impact in the transcriptome.
Por:
Garcia P, Fernandez-Hernandez R, Cuadrado A, Coca I, Gomez A, Maqueda M, Latorre-Pellicer A, Puisac B, Ramos FJ, Sandoval J, Esteller M, Mosquera JL, Rodriguez J, Pié J, Losada A and Queralt E
Publicada:
27 jul 2021
Ahead of Print:
27 jul 2021
Resumen:
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.
Filiaciones:
Garcia P:
Cell Cycle Group, Institut d'Investigacions Biomèdica de Bellvitge (IDIBELL), Av. Gran Via de L'Hospitalet 199-203, Barcelona, Spain.
Instituto de Biología Funcional y Genómica, CSIC/Universidad de Salamanca and Departamento de Microbiología y Genética, Universidad de Salamanca, Salamanca, Spain.
Fernandez-Hernandez R:
Cell Cycle Group, Institut d'Investigacions Biomèdica de Bellvitge (IDIBELL), Av. Gran Via de L'Hospitalet 199-203, Barcelona, Spain
Cuadrado A:
Chromosome Dynamics Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
Coca I:
Research and Development Department, qGenomics Laboratory, Esplugues de Llobregat, Spain
Gomez A:
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain
Grup de Recerca de Reumatologia, Parc Científic de Barcelona, Barcelona, Spain
Maqueda M:
Bioinformatics Unit, Institut d'Investigacions Biomèdica de Bellvitge (IDIBELL), Av. Gran Via de L'Hospitalet 199-203, Barcelona, Spain
Latorre-Pellicer A:
Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology and Paediatrics, School of Medicine, University of Zaragoza, CIBERER-GCV02 and IISAragon, Zaragoza, Spain
Puisac B:
Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology and Paediatrics, School of Medicine, University of Zaragoza, CIBERER-GCV02 and IISAragon, Zaragoza, Spain
Ramos FJ:
Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology and Paediatrics, School of Medicine, University of Zaragoza, CIBERER-GCV02 and IISAragon, Zaragoza, Spain
Sandoval J:
Biomarkers and Precision Medicine Unit (UByMP) and Epigenomics Core Facility, Health Research Institute La Fe (IISLaFe), Valencia, Spain
:
Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Catalonia, Spain
Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain
Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain
Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona, Barcelona, Catalonia, Spain
Mosquera JL:
Bioinformatics Unit, Institut d'Investigacions Biomèdica de Bellvitge (IDIBELL), Av. Gran Via de L'Hospitalet 199-203, Barcelona, Spain
Rodriguez J:
Research and Development Department, qGenomics Laboratory, Esplugues de Llobregat, Spain
Pié J:
Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology and Paediatrics, School of Medicine, University of Zaragoza, CIBERER-GCV02 and IISAragon, Zaragoza, Spain
Losada A:
Chromosome Dynamics Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
Queralt E:
Instituto de Biomedicina de Valencia (IBV-CSIC), Valencia, Spain.
Green Published, gold
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