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

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

Fecha de publicación: Fecha Ahead of Print:

Autores de IIS La Fe

Participantes ajenos a IIS La Fe

  • Garcia, P
  • Fernandez-Hernandez, R
  • Cuadrado, A
  • Coca, I
  • Gomez, A
  • Maqueda, M
  • Latorre-Pellicer, A
  • Puisac, B
  • Ramos, FJ
  • Esteller, M
  • Mosquera, JL
  • Rodriguez, J
  • Pié, J
  • Losada, A
  • Queralt, E

Grupos

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. Patients with Cornelia de Lange Syndrome (CdLS) often have mutations in cohesin and its regulators; however, the molecular mechanism driving CdLS phenotypes is not well established. Here the authors reveal system skeletal organization genes are downregulated and show that cohesin and its loader Nipbl have altered and decreased genome-wide localization.

Datos de la publicación

ISSN/ISSNe:
2041-1723, 2041-1723

Nature Communications  NATURE PORTFOLIO

Tipo:
Article
Páginas:
4551-4551
PubMed:
34315879
Factor de Impacto:
4,846 SCImago ℠
Cuartil:
Q1 SCImago ℠

Citas Recibidas en Web of Science: 35

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Keywords

  • SISTER-CHROMATID COHESION; GENE-EXPRESSION; DNA; MUTATIONS; CTCF; COMPLEX; DOMAINS; BINDING; SCC2; ESTABLISHMENT

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