Genetic coupling of enhancer activity and connectivity in gene expression control
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...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-55900-3 |
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| author | 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 Mikhail Spivakov |
| author_facet | 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 Mikhail Spivakov |
| author_sort | Helen Ray-Jones |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ac0c0e0bb2cb4d449b1016197acc58fd |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-ac0c0e0bb2cb4d449b1016197acc58fd2025-02-02T12:32:16ZengNature PortfolioNature Communications2041-17232025-01-0116112610.1038/s41467-025-55900-3Genetic coupling of enhancer activity and connectivity in gene expression controlHelen Ray-Jones0Chak Kei Sung1Lai Ting Chan2Alexander Haglund3Pavel Artemov4Monica Della Rosa5Luminita Ruje6Frances Burden7Roman Kreuzhuber8Anna Litovskikh9Eline Weyenbergh10Zoï Brusselaers11Vanessa Xue Hui Tan12Mattia Frontini13Chris Wallace14Valeriya Malysheva15Leonardo Bottolo16Elena Vigorito17Mikhail Spivakov18MRC Laboratory of Medical SciencesMRC Laboratory of Medical SciencesComputational Neurobiology, VIB Center for Molecular Neurology, VIBDepartment of Brain Sciences, Faculty of Medicine, Imperial College LondonMRC Laboratory of Medical SciencesMRC Laboratory of Medical SciencesMRC Laboratory of Medical SciencesDepartment of Haematology, University of Cambridge, Cambridge Biomedical CampusDepartment of Haematology, University of Cambridge, Cambridge Biomedical CampusMRC Laboratory of Medical SciencesComputational Neurobiology, VIB Center for Molecular Neurology, VIBComputational Neurobiology, VIB Center for Molecular Neurology, VIBMRC Laboratory of Medical SciencesDepartment of Haematology, University of Cambridge, Cambridge Biomedical CampusCambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, University of CambridgeMRC Laboratory of Medical SciencesMRC Biostatistics Unit, School of Clinical Medicine, University of CambridgeMRC Biostatistics Unit, School of Clinical Medicine, University of CambridgeMRC Laboratory of Medical SciencesAbstract 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.https://doi.org/10.1038/s41467-025-55900-3 |
| spellingShingle | 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 Mikhail Spivakov Genetic coupling of enhancer activity and connectivity in gene expression control Nature Communications |
| title | Genetic coupling of enhancer activity and connectivity in gene expression control |
| title_full | Genetic coupling of enhancer activity and connectivity in gene expression control |
| title_fullStr | Genetic coupling of enhancer activity and connectivity in gene expression control |
| title_full_unstemmed | Genetic coupling of enhancer activity and connectivity in gene expression control |
| title_short | Genetic coupling of enhancer activity and connectivity in gene expression control |
| title_sort | genetic coupling of enhancer activity and connectivity in gene expression control |
| url | https://doi.org/10.1038/s41467-025-55900-3 |
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