Article | Published:

Deciphering molecular circuits from genetic variation underlying transcriptional responsiveness to stimuli

Nature Biotechnology volume 31, pages 342349 (2013) | Download Citation

Abstract

Individual genetic variation affects gene responsiveness to stimuli, often by influencing complex molecular circuits. Here we combine genomic and intermediate-scale transcriptional profiling with computational methods to identify variants that affect the responsiveness of genes to stimuli (responsiveness quantitative trait loci or reQTLs) and to position these variants in molecular circuit diagrams. We apply this approach to study variation in transcriptional responsiveness to pathogen components in dendritic cells from recombinant inbred mouse strains. We identify reQTLs that correlate with particular stimuli and position them in known pathways. For example, in response to a virus-like stimulus, a trans-acting variant responds as an activator of the antiviral response; using RNA interference, we identify Rgs16 as the likely causal gene. Our approach charts an experimental and analytic path to decipher the mechanisms underlying genetic variation in circuits that control responses to stimuli.

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Acknowledgements

We thank C. (Jimmie) Ye, J. Pickerel, M. Daly and E. Lander for comments and discussions. I.G.-V. and I.A. were supported by Human Frontiers Science Program postdoctoral fellowships. Work was supported by Howard Hughes Medical Institute, a US National Institutes of Health PIONEER award, a Burroughs-Wellcome Fund Career Award at the Scientific Interface (A.R.), a Center for Excellence in Genome Science grant 5P50HG006193-02 from the National Human Genome Research Institute (N.H. and A.R.), the Klarman Cell Observatory at the Broad Institute (A.R.), the New England Regional Center for Excellence/Biodefense and Emerging Infectious Disease U54 AI057159 (N.H.), the Israeli Centers of Research Excellence (I-CORE) Gene Regulation in Complex Human Disease, Center No. 41/11 (I.G.-V., R.W. and Y.S.), the Human Frontiers Science Program Career Development Award and an Israeli Science Foundation Bikura Institutional Research Grant Program (I.A.) and the Edmond J. Safra Center for Bioinformatics at Tel-Aviv University (R.W. and Y.S.). A.R. is a fellow of the Merkin Foundation for Stem Cell Research at the Broad Institute. I.G.-V. is a Faculty Fellow of the Edmond J. Safra Center for Bioinformatics at Tel Aviv University and an Alon Fellow.

Author information

Affiliations

  1. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Irit Gat-Viks
    • , Nicolas Chevrier
    • , Thomas Eisenhaure
    • , Raktima Raychowdhury
    • , Nir Hacohen
    • , Ido Amit
    •  & Aviv Regev
  2. Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.

    • Irit Gat-Viks
    • , Roni Wilentzik
    •  & Yael Steuerman
  3. Graduate Program in Immunology, Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, USA.

    • Nicolas Chevrier
  4. FAS Center for Systems Biology, Harvard University, Cambridge, Massachusetts, USA.

    • Nicolas Chevrier
  5. Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown, Massachusetts, USA.

    • Thomas Eisenhaure
    •  & Nir Hacohen
  6. Departments of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA.

    • Alex K Shalek
  7. Department of Physics, Harvard University, Cambridge, Massachusetts, USA.

    • Alex K Shalek
  8. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

    • Nir Hacohen
  9. Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.

    • Ido Amit
  10. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Aviv Regev

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Contributions

I.G.-V., I.A. and A.R. conceived and designed the study. N.C., T.E., R.R., A.S. and I.A. conducted the experiments. I.G.-V. and A.R. conceived computational methods. I.G.-V., R.W. and Y.S. conceived, developed and implemented the computational methods. N.H. participated in study design and interpretation. I.G.-V., I.A. and A.R. wrote the manuscript with input from all the authors.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Irit Gat-Viks or Ido Amit or Aviv Regev.

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DOI

https://doi.org/10.1038/nbt.2519

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