Chromatin three-dimensional interactions mediate genetic effects on gene expression

RE: Regulatory Elements

ChIP-seq: chromatin immunoprecipitation sequencing 

CRD:  cis-regulatory domain

TAD: topologically associated domains

TRH: trans-regulatory hubs

eQTL: expression quantitative trait loci

we still have a poor understanding of how noncoding genetic variations affect the regulatory machinery, which regulatory elements (REs) they perturb, and how their effects propagate along regulatory interactions.

TRHs are consistent with a higher-order chromatin organization into A and B nuclear compartments and show a signal of allelic coordination, suggesting that some of the trans associations are not transcriptionally mediated and result from a complex and higher-order 3D nucleus organization.

CRDs and TRHs essentially delimit sets of active REs involved in the expression of most genes and provide a dense genome-wide map linking REs and genes. 

these links vary substantially across cell types and are key factors involved in the cis and trans coexpression of genes.

Natural genetic variation outside of protein coding regions affects multiple molecular phenotypes that can differ across individuals. 

genomic variation affects proximal (cis) or distal (trans) gene regulation

Clustering regulatory elements and activity across individuals reveals genomic structures termed cis-regulatory domains and trans-regulatory hubs that affect gene expression. Associations between these structures and genes within and across chromosomes contribute to links between noncoding genetic variation and gene expression.

Overall, our study reveals the complexity and specificity of the cis- and trans-regulatory circuitry and its perturbation by genetic variations.

PubMed 22 citations

ResearchGate 50 citations