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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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Shared genetic effects on chromatin and gene expression indicate a role for enhancer priming in immune response
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Journal Article
Shared genetic effects on chromatin and gene expression indicate a role for enhancer priming in immune response
2018
Overview
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.
Analysis of chromatin accessibility and expression quantitative trait loci in stimulated or naïve macrophages identifies loci that constitutively alter chromatin but affect expression only after stimulation, thus indicating an effect on enhancer priming.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ 13/31
/ 38/43
/ 38/91
/ 45/100
/ Animal Genetics and Genomics
/ Biomedical and Life Sciences
/ Enhancer Elements, Genetic - genetics
/ Female
/ Genomes
/ Humans
/ Immunity, Cellular - genetics
/ Male
/ Principal components analysis
/ Salmonella Infections - genetics
/ Salmonella Infections - immunology
/ Salmonella Infections - metabolism
/ Salmonella typhimurium - immunology
