Genetic coupling of enhancer activity and connectivity in gene expression control
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.
Authors
- Chris Wallace (ORCID: https://orcid.org/0000-0001-9755-1703)
- Elena Vigorito (ORCID: https://orcid.org/0000-0001-6230-3849)
- Leonardo Bottolo (ORCID: https://orcid.org/0000-0002-6381-2327)
- Pavel Artemov (ORCID: https://orcid.org/0000-0001-6699-6400)
- Roman Kreuzhuber (ORCID: https://orcid.org/0000-0002-0762-0806)
- Helen Ray-Jones (ORCID: https://orcid.org/0000-0002-8884-6865)
- Changmin Sung (ORCID: https://orcid.org/0000-0001-7318-7353)
- Monica Della Rosa (ORCID: https://orcid.org/0000-0002-0626-4598)
- Alexander Haglund (ORCID: https://orcid.org/0000-0003-0404-0723)
- Mattia Frontini (ORCID: https://orcid.org/0000-0001-8074-6299)
- Mikhail Spivakov (ORCID: https://orcid.org/0000-0002-0383-3943)
- Luminiţa Ruje
- Valeriya Malysheva (ORCID: https://orcid.org/0000-0002-0919-7845)
- Eline Weyenbergh
- Zoï Brusselaers
- Frances Burden (ORCID: https://orcid.org/0000-0001-6266-1304)
- Anna Litovskikh (ORCID: https://orcid.org/0000-0002-7017-1767)
- Lai Ting Chan (ORCID: https://orcid.org/0009-0008-2600-1710)
- Vanessa Xue Hui Tan
Institutions
- National Health Service (GB)
- Turing Institute (GB)
- European Bioinformatics Institute (GB)
- NHS Blood and Transplant (GB)
- University of Antwerp (BE)
- University of Kent (GB)
- University of Exeter (GB)
- University of Cambridge (GB)
- Federal Department of Finance (CH)
- Helmholtz Zentrum München (DE)
- Cambridge School (PT)
- Antwerp University Hospital (BE)
- The Alan Turing Institute (GB)
- VIB-UAntwerp Center for Molecular Neurology (BE)
- MRC Biostatistics Unit (GB)
- Swiss Federal Railways (CH)
- MRC London Institute of Medical Sciences (GB)
- Imperial College London (GB)
- Ludwig-Maximilians-Universität München (DE)
- University of Hong Kong (HK)
- Erasmus University Rotterdam (NL)
- Cytel (United States) (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-01-27
- DOI
- https://doi.org/10.1038/s41467-025-55900-3
- Citations
- 7
- Primary Topic
- Genomics and Chromatin Dynamics
- Type
- article
- Field-Weighted Citation Impact
- 5.64
Funders
- Wellcome
- NHS Blood and Transplant
- Wellcome Trust
- National Institute for Health and Care Research
- British Heart Foundation
- Department of Health and Social Care
- NIHR BioResource
- Medical Research Council
- Engineering and Physical Sciences Research Council
- NIHR Cambridge Biomedical Research Centre