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| Página principal > Artículos > Artículos publicados > Disruption of NIPBL/Scc2 in Cornelia de Lange Syndrome provokes cohesin genome-wide redistribution with an impact in the transcriptome |
(Centro Nacional de Investigaciones Oncológicas) (Institut d'Investigació Biomèdica de Bellvitge) (Universidad de Zaragoza) (Universidad de Zaragoza) (Universidad de Zaragoza) (Instituto de Investigación Sanitaria La Fe) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut d'Investigació Biomèdica de Bellvitge) (Centro Nacional de Investigaciones Oncológicas) (Instituto de Biomedicina de Valencia (IBV-CSIC))| Fecha: | 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. |
| Ayudas: | Instituto de Salud Carlos III CA18/00045 Instituto de Salud Carlos III PTA2018-016371-I Instituto de Salud Carlos III B32_17R Instituto de Salud Carlos III PI19/01860 Ministerio de Economía y Competitividad BFU2013-43132-P Ministerio de Economía y Competitividad BFU2016-77975-R Ministerio de Economía y Competitividad BFU2016-79841 Fundació la Marató de TV3 101030 FMTV3 |
| Nota: | We thank all the members of our laboratory for discussing this work and for their critical reading of the manuscript. We thank Diana Garcia for her technical support. We thank the CERCA Program/Generalitat de Catalunya for institutional support. This work was funded by the Spanish Ministry of Economy, Industry and Competitiveness (MINECO), which is part of the State Agency, through the projects BFU2013-43132-P and BFU2016-77975-R to E.Q., and BFU2016-79841 to A.L. (co-funded by the European Regional Development Fund, ERDF, a way to build Europe) and the MaratóTV3 (101030 FMTV3) to E.Q. A.L.-P., B.P., F.R., and J.P. are funded by the Spanish Ministry of Health ISCIII-FIS (Ref. PI19/01860) and by the Gobierno de Aragon (Ref. B32_17R) and belong to the GCV02 of CIBERER. J.L.M. is a recipient of a grant from the Instituto Carlos III, which is part of the State Agency, grant number CA18/00045 (co-funded by the European Regional Development Fund, ERDF, a way to build Europe) and M.M. is a recipient of the fellowship "Personal Técnico de Apoyo" number PTA2018-016371-I funded by the Spanish Ministry of Science, Innovation and Universities (MCIU), which is part of the State Agency. |
| Derechos: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Lengua: | Anglès |
| Documento: | Article ; recerca ; Versió publicada |
| Materia: | Cell Cycle Proteins ; Cell Differentiation ; Chromatin ; Chromosomal Proteins, Non-Histone ; De Lange Syndrome ; Fibroblasts ; Genome, Human ; Humans ; Protein Stability ; Transcriptome |
| Publicado en: | Nature communications, Vol. 12 Núm. 1 (january 2021) , p. 4551, ISSN 2041-1723 |
