Abstract
The 3D conformation of the chromatin creates complex networks of noncoding regulatory regions (distal elements) and promoters impacting gene regulation. Despite the importance of the role of noncoding regions in complex diseases, little is known about their interplay within regulatory hubs and implication in multigenic diseases such as schizophrenia. Here we show that cis-regulatory hubs (CRHs) in neurons highlight functional interactions between distal elements and promoters, providing a model to explain epigenetic mechanisms involved in complex diseases. CRHs represent a new 3D model, where distal elements interact to create a complex network of active genes. In a disease context, CRHs highlighted strong enrichments in schizophrenia-associated genes, schizophrenia-associated SNPs, and schizophrenia heritability compared with equivalent structures. Finally, CRHs exhibit larger proportions of genes differentially expressed in schizophrenia compared with promoter-distal element pairs or TADs. CRHs thus capture causal regulatory processes improving the understanding of complex disease etiology such as schizophrenia. These multiple lines of genetic and statistical evidence support CRHs as 3D models to study dysregulation of gene expression in complex diseases more generally.
Highlights
The etiology of complex diseases involves a broad range of causal factors, both genetic and environmental, leading to gene expression changes (Vliet et al, 2007; Do et al, 2017)
in SNP and heritability enrichments were downloaded from the PGC site https://www.med.unc.edu/pgc/ results-and-downloads
the clumped SNP file keeping the SNPs with the highest association signal with schizophrenia
Summary
The etiology of complex diseases involves a broad range of causal factors, both genetic and environmental, leading to gene expression changes (Vliet et al, 2007; Do et al, 2017). Models currently used in the etiology of complex diseases suggest that most risk variants are located within noncoding regions explaining a large portion of the heritability (Maurano et al, 2012). Most risk variants are enriched in distal noncoding regions, disturbing the tissue-specific transcriptional program, and playing a key role in disease etiology (Zhang & Lupski, 2015). Consistent with a role of noncoding regions in complex phenotypes, there is strong evidence on the involvement of 3D chromatin conformation in gene regulation. In addition to chromatin loops connecting promoters to distal noncoding regions (Gorkin et al, 2014; Bouwman & de Laat, 2015; Dekker & Mirny, 2016), the genome is parsed into larger domains including topologically associating domains (TADs) (Dixon et al, 2012) and A/B compartments (Lieberman-Aiden et al, 2009). Precisely identifying which genes are affected by a risk variant remains a challenge
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
