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Ray-Jones, H.* ; Sung, C.K.* ; Chan, L.T.* ; Haglund, A.* ; Artemov, P.* ; Della Rosa, M.* ; Ruje, L.* ; Burden, F.* ; Kreuzhuber, R.* ; Litovskikh, A. ; Weyenbergh, E.* ; Brusselaers, Z.* ; Tan, V.X.H.* ; Frontini, M.* ; Wallace, C.* ; Malysheva, V.* ; Bottolo, L.* ; Vigorito, E.* ; Spivakov, M.*

Genetic coupling of enhancer activity and connectivity in gene expression control.

Nat. Commun. 16:970 (2025)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Range Chromatin Interactions; R/bioconductor Package; Transcription Factors; Genotype Imputation; Sex-differences; Eqtl Analysis; Variants; Binding; Model; Links

ISSN (print) / ISBN 2041-1723

e-ISSN 2041-1723

Journal Nature Communications

Quellenangaben Volume: 16, Issue: 1, Article Number: 970

Publisher Nature Publishing Group

Publishing Place London

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Computational Biology (ICB)

Grants RCUK | Medical Research Council (MRC)
NIHR Exeter Biomedical Research Centre
BHF Cambridge Centre for Research Excellence
British Heart Foundation (BHF)
NIHR Cambridge Biomedical Research Centre
Marmaduke Sheild Fund
Alan Turing Institute under the Engineering and Physical Sciences Research Council (EPSRC)
MRC
Medical Research Council (MRC) of the UK through MRC
NHS Blood and Transplant, and Health Data Research UK as part of the Digital Innovation Hub Programme
UK's National Institute for Health and Care Research (NIHR)
Wellcome Trust