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Shared genetic effects on chromatin and gene expression indicate a role for enhancer priming in immune response
Open accessPublished version of a preprint
Abstract
Regulatory variants are often context specific, modulating gene expression in a subset of possible cellular states. Although these genetic effects can play important roles in disease, the molecular mechanisms underlying context specificity are poorly understood. Here, we identified shared quantitative trait loci (QTLs) for chromatin accessibility and gene expression in human macrophages exposed to IFNγ, Salmonella and IFNγ plus Salmonella. We observed that ~60% of stimulus-specific expression QTLs with a detectable effect on chromatin altered the chromatin accessibility in naive cells, thus suggesting that they perturb enhancer priming. Such variants probably influence binding of cell-type-specific transcription factors, such as PU.1, which can then indirectly alter the binding of stimulus-specific transcription factors, such as NF-κB or STAT2. Thus, although chromatin accessibility assays are powerful for fine-mapping causal regulatory variants, detecting their downstream effects on gene expression will be challenging, requiring profiling of large numbers of stimulated cellular states and time points.
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“Second, it has been recently shown that the variants associated with chromatin accessibility capture stimulus-sensitive signals and explain a significant proportion of heritability, even more so than eQTLs47,48.”
From A computational tool (H-MAGMA) for improved prediction of brain-disorder risk genes by incorporating brain chromatin interaction profiles (2020) · cites this paper as [47]
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Metadata
- Authors
- HIPSCI Consortium, Alasoo, K., Rodrigues, J., Mukhopadhyay, S., Knights, A. J., Mann, A. L., Kundu, K., Hale, C., Dougan, G., & Gaffney, D. J.
- Affiliations
- Wellcome Sanger Institute (GB)
- University of Cambridge (GB)
- Corresponding author
- Alasoo, Kaur
- Gaffney, Daniel J.
- ORCID
- Venue
- Nature Genetics
- Published
- 2018-01-29
- Volume
- 50
- Issue
- 3
- Pages
- 424-431
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC6548559
- OpenAlex
- W2785443776
- Cited by
- 338
- References
- 74
- Citations by year
- 2026: 37 · 2025: 45 · 2024: 50 · 2023: 45 · 2022: 35 · 2021: 48 · 2020: 36 · 2019: 33 · 2018: 7
- FWCI
- 11.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Research Portal (King's College London) (submittedVersion)
- Apollo
- Funders
- Life Technologies Corporation
- Wellcome Trust (WT099754, 098503, WT 098051, 098051)
- LifeArc
- Eesti Teadusagentuur
- Medical Research Council (MC_PC_12026)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- chromatin accessibility, expression quantitative trait loci, macrophages, interferon-gamma, Salmonella, immune response, regulatory variants, PU.1, NF-κB, STAT2, transcription factor binding, quantitative trait loci
- MeSH terms
- Cells, Cultured, Chromatin, Enhancer Elements, Genetic, Female, Humans, Immunity, Cellular, Macrophages, Male, Protein Binding, Salmonella Infections, Salmonella typhimurium, Transcription Factors, Gene Expression, Quantitative Trait Loci
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