Connected Gene Communities Underlie Transcriptional Changes in Cornelia de Lange Syndrome

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 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.

Defining the Transcriptional Ecosystem

“…The association of similar individuals (or DNA elements) in a defined area creates populations. As we and others have shown, the interplay between these populations of DNA elements defines communities (Boudaoud et al, 2017;Fanucchi et al, 2013;Li et al, 2012). Each member of a natural ecosystem shares nutrients, air, water, and all essential abiotic components to survive and maintain homeostasis.…”

“…The number of sites with active transcription in the nucleus is smaller than the number of transcribed coding and noncoding genes, supporting the presence of multiple genes in each defined area (Chakalova and Fraser, 2010;Feuerborn and Cook, 2015;Rieder et al, 2012). These pieces of physical evidence are corroborated by the observation that connected genes are transcriptionally coregulated (Boudaoud et al, 2017;Fanucchi et al, 2013;Osborne et al, 2004). This high level of organization is important for different aspects of gene regulation, but questions remain regarding the dynamic regulation of genes sharing the same physical environment.…”

Regulation of inflammation in diabetes: From genetics to epigenomics evidence

“…The understanding of nuclear architecture has improved dramatically over the past decade. The latest reports corroborate the formation of multi-enhancer contacts, variously called cis -regulatory domains [ 109 , 110 ], activation hubs [ 111 ], interacting triplets [ 112 ], connected gene communities [ 113 ] or 3D cliques [ 114 ], all contained within topologically-associated domains (TADs) [ 115 ]. Despite these observations, it remains unclear how multi-enhancer interactions mediated by metabolic- and pro-inflammatory stimuli are associated with diabetes onset and progression.…”

Behavioural and psychological characteristics in Pitt-Hopkins syndrome: a comparison with Angelman and Cornelia de Lange syndromes

“…Heterozygous mutation of the NIPBL gene, located on chromosome 5p13 (approximately 65% of cases, with further cases being due to mosaicism). Less commonly caused by mutations in SMC3, SMC1A, HDAC8 and RED21 genes (11% of cases) [44].…”

“…Hyper-responsitivity: typical range (14-29), at risk range (30)(31)(32)(33)(34) and deficient range . Sensory seeking: typical range , at risk range (39)(40)(41)(42)(43)(44)(45)(46)(47) and deficient range (48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65). Social contexts: typical range (10)(11)(12)(13)(14)(15)(16)(17)(18), at risk range (19)(20)(21) and deficient range .…”