Connected Gene Communities Underlie Transcriptional Changes in Cornelia de Lange Syndrome. Issue 1 (5th July 2017)

• Record Type: Journal Article
• Authors: Boudaoud, Imène; Fournier, Éric; Baguette, Audrey; Vallée, Maxime; Lamaze, Fabien C; Droit, Arnaud; Bilodeau, Steve
• Is Part Of: Genetics. Volume 207:Issue 1(2017)
• Page Start: 139
• Page End: 151
• Publication Date: 2017-07-05
• Subjects: chromosome architecture -- transcription regulation -- epigenomics -- noncoding regulatory regions -- transcriptional networks; Genetics -- Periodicals; 576.5
• DOI: 10.1534/genetics.117.202291
• Languages: English
• ISSNs: 0016-6731

Abstract

Abstract: 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 NIPBL and the cohesin subunit SMC1A . 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.