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

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

doi:10.1038/s41467-021-24808-z

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.

Highlights

Cornelia de Lange syndrome (CdLS) is a rare disease affecting multiple organs and systems during development
The acetylation of SMC3 was similar in cycling and quiescent cells indicating that non-cohesive complexes are acetylated
Our results clearly indicate that the chromatin regions, where SMC1A is gained and lost, are structurally very different: while SMC1A tends to be gained at NIPBL-occupied, CCCTCbinding factor (CTCF)-free, moderately accessible regions; SMC1A tends to be lost at regions where it is usually found: CTCF-occupied and NIPBL-free regions

Summary

Introduction

Cornelia de Lange syndrome (CdLS) is a rare disease affecting multiple organs and systems during development. Mutations in the cohesin loader, NIPBL/Scc[2], were first described and are the most frequent in clinically diagnosed CdLS patients. Cornelia de Lange syndrome (CdLS; OMIM 122470, 300590, 610759, 300882, 614701), known as Brachmann-de Lange syndrome), is a rare, sporadic, and genetically heterogeneous autosomal- or X-linked-dominant disorder affecting multiple organs and systems during development The molecular mechanisms of CdLS are not well understood, the patient phenotypes suggest that the function of cohesin and NIPBL in chromatin structure becomes deregulated, thereby affecting gene transcription. The core of the cohesin complex is a ring-shaped heterotrimer formed by evolutionarily conserved subunits: two SMC (structural maintenance of chromosomes) proteins SMC1A and SMC3 and the kleisin protein RAD21 ( called MDC1 or SCC1)[23,24,34]. Cohesin association with chromatin is regulated by the HAWKs proteins (HEAT repeat containing proteins Associated With Kleisins) whose functions are to open, close, or stabilize the cohesin ring: STAG1/

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Conclusion