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

Garcia, Patricia ; Fernandez-Hernandez, Rita ; Cuadrado, Ana ; Coca, Ignacio ; Gomez, Antonio ; Maqueda, Maria ; Latorre-Pellicer, Ana (Universidad de Zaragoza) ; Puisac, Beatriz ; Ramos, Feliciano J. (Universidad de Zaragoza) ; Sandoval, Juan ; Esteller, Manel ; Mosquera, Jose Luis ; Rodriguez, Jairo ; Pié, J. (Universidad de Zaragoza) ; Losada, Ana ; Queralt, Ethel

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.

Idioma: Inglés

DOI: 10.1038/s41467-021-24808-z

Año: 2021

Publicado en: Nature communications 12 (2021), 4551 [15 pp.]
ISSN: 2041-1723

Factor impacto JCR: 17.694 (2021)

Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 6 / 74 = 0.081 (2021) - Q1 - T1

Factor impacto CITESCORE: 23.2 - Biochemistry, Genetics and Molecular Biology (Q1) - Physics and Astronomy (Q1)

Factor impacto SCIMAGO: 4.846 - Chemistry (miscellaneous) (Q1) - Biochemistry, Genetics and Molecular Biology (miscellaneous) (Q1)

Financiación: info:eu-repo/grantAgreement/ES/DGA/B32-17R
Financiación: info:eu-repo/grantAgreement/ES/FIS/PI19-01860
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/CA18-00045
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/PI19-01860
Financiación: info:eu-repo/grantAgreement/ES/MICIU/PTA2018-016371-I
Financiación: info:eu-repo/grantAgreement/ES/MINECO/BFU2013-43132-P
Financiación: info:eu-repo/grantAgreement/ES/MINECO/BFU2016-77975-R
Financiación: info:eu-repo/grantAgreement/ES/MINECO/BFU2016-79841

Tipo y forma: Article (Published version)

Área (Departamento): Área Fisiología (Dpto. Farmac.Fisiol.y Med.L.F.)
Área (Departamento): Área Pediatría (Dpto. Microb.Ped.Radio.Sal.Pú.)