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

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.

journal_name

Nat Genet

journal_title

Nature genetics

authors

Alasoo K,Rodrigues J,Mukhopadhyay S,Knights AJ,Mann AL,Kundu K,HIPSCI Consortium.,Hale C,Dougan G,Gaffney DJ

doi

10.1038/s41588-018-0046-7

subject

Has Abstract

pub_date

2018-03-01 00:00:00

pages

424-431

issue

3

eissn

1061-4036

issn

1546-1718

pii

10.1038/s41588-018-0046-7

journal_volume

50

pub_type

杂志文章

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