PT  - JOURNAL ARTICLE
AU  - Kaur Alasoo
AU  - Julia Rodrigues
AU  - Subhankar Mukhopadhyay
AU  - Andrew J. Knights
AU  - Alice L. Mann
AU  - Kousik Kundu
AU  - HIPSCI Consortium
AU  - Christine Hale
AU  - Gordon Dougan
AU  - Daniel J. Gaffney
TI  - Shared genetic effects on chromatin and gene expression reveal widespread enhancer priming in immune response
AID  - 10.1101/102392
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 102392
4099  - http://biorxiv.org/content/early/2017/05/18/102392.short
4100  - http://biorxiv.org/content/early/2017/05/18/102392.full
AB  - Noncoding regulatory variants are often highly context-specific, modulating gene expression in a small subset of possible cellular states. Although these genetic effects are likely to play important roles in disease, the molecular mechanisms underlying context-specificity are not well understood. Here, we identify shared quantitative trait loci (QTLs) for chromatin accessibility and gene expression (eQTLs) and show that a large fraction (∼60%) of eQTLs that appear following macrophage immune stimulation alter chromatin accessibility in unstimulated cells, suggesting they perturb enhancer priming. We show that such variants are likely to influence the binding of cell type specific transcription factors (TFs), such as PU.1, which then indirectly alter the binding of stimulus-specific TFs, such as NF-κB or STAT2. Our results imply that, although chromatin accessibility assays are powerful for fine mapping causal noncoding variants, detecting their downstream impact on gene expression will be challenging, requiring profiling of large numbers of stimulated cellular states and timepoints.