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

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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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We thank L. Parts, J. Schwartzentruber, C. Wallace, L. Milani, K. Lepik and H. Peterson for helpful comments on the manuscript. We thank R. Nelson for assistance and early access to HipSci iPSC lines. We thank R. Kreuzhuber for providing access to the imputed genotype data from the Fairfax study. We thank C. D. Brown for helpful comments on the manuscript. We also thank WTSI DNA Pipelines and Cytometry Core Facility for their sequencing and flow cytometry services. This work was supported by Wellcome Trust grant WT098051 (G.D. and D.J.G.). K.A. was supported by a PhD fellowship from the Wellcome Trust (WT099754/Z/12/Z) and a postdoctoral fellowship from the Estonian Research Council (MOBJD67). The iPSC lines were generated at the Wellcome Trust Sanger Institute, under the Human Induced Pluripotent Stem Cell Initiative funded by a strategic award (WT098503) from the Wellcome Trust and Medical Research Council. We also acknowledge Life Science Technologies Corporation as the provider of cytotune.

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Author notes

    • Kaur Alasoo

    Present address: Institute of Computer Science, University of Tartu, Tartu, Estonia

  1. A full list of members and affiliations appears in the Supplementary Note


  1. Wellcome Trust Sanger Institute, Hinxton, UK

    • Kaur Alasoo
    • , Julia Rodrigues
    • , Subhankar Mukhopadhyay
    • , Andrew J. Knights
    • , Alice L. Mann
    • , Kousik Kundu
    • , Christine Hale
    • , Gordon Dougan
    •  & Daniel J. Gaffney
  2. Department of Haematology, University of Cambridge, Cambridge, UK

    • Kousik Kundu


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  1. HIPSCI Consortium


    K.A. and D.J.G. wrote the paper with input from all authors. K.A. and J.R. performed the macrophage differentiation experiments. J.R. and A.J.K. performed the chromatin accessibility assays. A.L.M. and K.K. assisted with disease colocalization and enrichment analysis. K.A., S.M. and C.H. optimized the stimulation experiments. K.A. analyzed the data. K.A., S.M., G.D. and D.J.G. designed the experiments. G.D. and D.J.G. supervised research. The HIPSCI Consortium generated and provided early accesss to the iPSC lines used in this work.

    Competing interests

    The authors declare no competing financial interests.

    Corresponding authors

    Correspondence to Kaur Alasoo or Daniel J. Gaffney.

    Supplementary information

    1. Supplementary Text and Figures

      Supplementary Figures 1–19, Supplementary Tables 2, 3 and 9, and Supplementary Note

    2. Life Sciences Reporting Summary

    3. Supplementary Tables

      Supplementary Tables 1 and 4–8