Cited by 353Genomics and Chromatin DynamicsGenetic Associations and EpidemiologyGenetic Mapping and Diversity in Plants and Animals

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Shared genetic effects on chromatin and gene expression indicate a role for enhancer priming in immune response

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HIPSCI Consortium, Alasoo, Kaur, Rodrigues, Julia, Mukhopadhyay, Subhankar, Knights, Andrew J., Mann, Alice L., Kundu, Kousik, Hale, Christine, Dougan, Gordon, Gaffney, Daniel J.·2018·Nature Genetics

DOI 10.1038/s41588-018-0046-7PMC PMC6548559

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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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Additional file 3 of Inferring cell-type-specific causal gene regulatory networks during human neurogenesis
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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: Alasoo, Kaur
Mukhopadhyay, Subhankar
Knights, Andrew J.
Mann, Alice L.
Kundu, Kousik
Gaffney, Daniel J.
Venue: Nature Genetics
Publisher: Springer Science and Business Media LLC
Published: 2018-01-29
Volume: 50
Issue: 3
Pages: 424-431
ISSN: 1061-4036 (ISSN-L)
1546-1718
DOI: 10.1038/s41588-018-0046-7
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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Shared genetic effects on chromatin and gene expression indicate a role for enhancer priming in immune response

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