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

15 páginas, 7 figuras. The online version contains supplementary material available at https://doi.org/10.1038/s41467-021-24808-z. The data that support this study are available from the corresponding authors upon reasonable request. ChIP-seq data generated in the course of this work have been deposited in the Gene Expression Omnibus (GEO) under the accession number GSE145966. Encode data for RAD21 (ENCFF361FUX) and MNase (ENCFF000VLK), GEO data for CTCF (GSM733672) and DNase (GSM816655), and Enhancer Atlas database for enhancer information (http://www.enhanceratlas.org/) were used for Fig. 5 and Supplementary Fig. 7. GEO data for CTCF (GSM935404) and the high-resolution Hi-C data for IMR90 cell lines (GSE63525) were used for the intra-TAD prediction tool for Fig. 7 and Supplementary Fig. 8. Other data supporting the findings of this study are available within the paper, its supplementary information files, and the source data file. Source data are provided with this paper. The custom scripts generated during the current study are available from https:// bitbucket.org/qgenomics/smc1a-nipbl.
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.
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 ISCIIIFIS (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.