Connected Gene Communities Underlie Transcriptional Changes in Cornelia de Lange Syndrome

Cornelia de Lange syndrome (CdLS) is a complex multisystem developmental disorder caused by mutations in cohesin subunits and regulators. While its precise molecular mechanisms are not well defined, they point toward a global deregulation of the transcriptional gene expression program. Cohesin is as...

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Bibliographic Details
Published in:Genetics (Austin) 2017-09, Vol.207 (1), p.139-151
Main Authors: Boudaoud, Imène, Fournier, Éric, Baguette, Audrey, Vallée, Maxime, Lamaze, Fabien C, Droit, Arnaud, Bilodeau, Steve
Format: Article
Language:English
Subjects:
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Cell Line, Tumor
Chromosomal Proteins, Non-Histone - genetics
Chromosomal Proteins, Non-Histone - metabolism
Chromosomes
Cohesin
Cohesion
Communities
De Lange syndrome
De Lange Syndrome - genetics
Deregulation
Developmental disabilities
Gene expression
Gene regulation
Gene Regulatory Networks
Genes
Genetics
Genome, Human
Genomes
Humans
Investigations
Molecular modelling
Mutation
Promoter Regions, Genetic
Proteins
Proteins - genetics
Regulatory sequences
RNA polymerase
Transcription
Transcriptome
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Summary:Cornelia de Lange syndrome (CdLS) is a complex multisystem developmental disorder caused by mutations in cohesin subunits and regulators. While its precise molecular mechanisms are not well defined, they point toward a global deregulation of the transcriptional gene expression program. Cohesin is associated with the boundaries of chromosome domains and with enhancer and promoter regions connecting the three-dimensional genome organization with transcriptional regulation. Here, we show that connected gene communities, structures emerging from the interactions of noncoding regulatory elements and genes in the three-dimensional chromosomal space, provide a molecular explanation for the pathoetiology of CdLS associated with mutations in the cohesin-loading factor and the cohesin subunit NIPBL and cohesin are important constituents of connected gene communities that are centrally positioned at noncoding regulatory elements. Accordingly, genes deregulated in CdLS are positioned within reach of NIPBL- and cohesin-occupied regions through promoter-promoter interactions. Our findings suggest a dynamic model where NIPBL loads cohesin to connect genes in communities, offering an explanation for the gene expression deregulation in the CdLS.
ISSN:1943-2631
0016-6731
1943-2631
DOI:10.1534/genetics.117.202291