Genetic coupling of enhancer activity and connectivity in gene expression control

Helen Ray-Jones (), Chak Kei Sung, Lai Ting Chan, Alexander Haglund, Pavel Artemov, Monica Della Rosa, Luminita Ruje, Frances Burden, Roman Kreuzhuber, Anna Litovskikh, Eline Weyenbergh, Zoï Brusselaers, Vanessa Xue Hui Tan, Mattia Frontini, Chris Wallace, Valeriya Malysheva, Leonardo Bottolo (), Elena Vigorito and Mikhail Spivakov ()
Additional contact information
Helen Ray-Jones: MRC Laboratory of Medical Sciences
Chak Kei Sung: MRC Laboratory of Medical Sciences
Lai Ting Chan: VIB
Alexander Haglund: Imperial College London
Pavel Artemov: MRC Laboratory of Medical Sciences
Monica Della Rosa: MRC Laboratory of Medical Sciences
Luminita Ruje: MRC Laboratory of Medical Sciences
Frances Burden: Cambridge Biomedical Campus
Roman Kreuzhuber: Cambridge Biomedical Campus
Anna Litovskikh: MRC Laboratory of Medical Sciences
Eline Weyenbergh: VIB
Zoï Brusselaers: VIB
Vanessa Xue Hui Tan: MRC Laboratory of Medical Sciences
Mattia Frontini: Cambridge Biomedical Campus
Chris Wallace: University of Cambridge
Valeriya Malysheva: MRC Laboratory of Medical Sciences
Leonardo Bottolo: University of Cambridge
Elena Vigorito: University of Cambridge
Mikhail Spivakov: MRC Laboratory of Medical Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-26

Abstract: Abstract Gene enhancers often form long-range contacts with promoters, but it remains unclear if the activity of enhancers and their chromosomal contacts are mediated by the same DNA sequences and recruited factors. Here, we study the effects of expression quantitative trait loci (eQTLs) on enhancer activity and promoter contacts in primary monocytes isolated from 34 male individuals. Using eQTL-Capture Hi-C and a Bayesian approach considering both intra- and inter-individual variation, we initially detect 19 eQTLs associated with enhancer-eGene promoter contacts, most of which also associate with enhancer accessibility and activity. Capitalising on these shared effects, we devise a multi-modality Bayesian strategy, identifying 629 “trimodal QTLs” jointly associated with enhancer accessibility, eGene promoter contact, and gene expression. Causal mediation analysis and CRISPR interference reveal causal relationships between these three modalities. Many detected QTLs overlap disease susceptibility loci and influence the predicted binding of myeloid transcription factors, including SPI1, GABPB and STAT3. Additionally, a variant associated with PCK2 promoter contact directly disrupts a CTCF binding motif and impacts promoter insulation from downstream enhancers. Jointly, our findings suggest an inherent genetic coupling of enhancer activity and connectivity in gene expression control relevant to human disease and highlight the regulatory role of genetically determined chromatin boundaries.

Date: 2025
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DOI: 10.1038/s41467-025-55900-3

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