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Effect of natural genetic variation on enhancer selection and function

Author

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  • S. Heinz

    (University of California, San Diego, 9500 Gilman Drive, Mail Code 0651, La Jolla, California 92093, USA)

  • C. E. Romanoski

    (University of California, San Diego, 9500 Gilman Drive, Mail Code 0651, La Jolla, California 92093, USA)

  • C. Benner

    (University of California, San Diego, 9500 Gilman Drive, Mail Code 0651, La Jolla, California 92093, USA
    Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA
    San Diego Center for Systems Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA)

  • K. A. Allison

    (University of California, San Diego, 9500 Gilman Drive, Mail Code 0651, La Jolla, California 92093, USA)

  • M. U. Kaikkonen

    (University of California, San Diego, 9500 Gilman Drive, Mail Code 0651, La Jolla, California 92093, USA
    A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, 70211 Kuopio, Finland)

  • L. D. Orozco

    (University of California, Los Angeles, 3000 Terasaki Life Sciences Building, Los Angeles, California 90095, USA)

  • C. K. Glass

    (University of California, San Diego, 9500 Gilman Drive, Mail Code 0651, La Jolla, California 92093, USA
    San Diego Center for Systems Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA
    University of California, San Diego, 9500 Gilman Drive, Mail Code 0651, La Jolla, California 92093, USA)

Abstract

The mechanisms by which genetic variation affects transcription regulation and phenotypes at the nucleotide level are incompletely understood. Here we use natural genetic variation as an in vivo mutagenesis screen to assess the genome-wide effects of sequence variation on lineage-determining and signal-specific transcription factor binding, epigenomics and transcriptional outcomes in primary macrophages from different mouse strains. We find substantial genetic evidence to support the concept that lineage-determining transcription factors define epigenetic and transcriptomic states by selecting enhancer-like regions in the genome in a collaborative fashion and facilitating binding of signal-dependent factors. This hierarchical model of transcription factor function suggests that limited sets of genomic data for lineage-determining transcription factors and informative histone modifications can be used for the prioritization of disease-associated regulatory variants.

Suggested Citation

  • S. Heinz & C. E. Romanoski & C. Benner & K. A. Allison & M. U. Kaikkonen & L. D. Orozco & C. K. Glass, 2013. "Effect of natural genetic variation on enhancer selection and function," Nature, Nature, vol. 503(7477), pages 487-492, November.
    • Handle: RePEc:nat:nature:v:503:y:2013:i:7477:d:10.1038_nature12615
    DOI: 10.1038/nature12615
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    Cited by:

    1. Claude Gérard & Laurane De Mot & Sabine Cordi & Jonathan van Eyll & Frédéric P Lemaigre, 2021. "Temporal dynamics of a CSF1R signaling gene regulatory network involved in epilepsy," PLOS Computational Biology, Public Library of Science, vol. 17(4), pages 1-20, April.
    2. Jingbo Qie & Yang Liu & Yunzhi Wang & Fan Zhang & Zhaoyu Qin & Sha Tian & Mingwei Liu & Kai Li & Wenhao Shi & Lei Song & Mingjun Sun & Yexin Tong & Ping Hu & Tao Gong & Xiaqiong Wang & Yi Huang & Bolo, 2022. "Integrated proteomic and transcriptomic landscape of macrophages in mouse tissues," Nature Communications, Nature, vol. 13(1), pages 1-23, December.
    3. Ben Arfi, Wissal & Ben Nasr, Imed & Khvatova, Tatiana & Ben Zaied, Younes, 2021. "Understanding acceptance of eHealthcare by IoT natives and IoT immigrants: An integrated model of UTAUT, perceived risk, and financial cost," Technological Forecasting and Social Change, Elsevier, vol. 163(C).
    4. Mingming Zhao & Jaimy Joy & Weiqiang Zhou & Supriyo De & William H Wood III & Kevin G Becker & Hongkai Ji & Ranjan Sen, 2018. "Transcriptional outcomes and kinetic patterning of gene expression in response to NF-κB activation," PLOS Biology, Public Library of Science, vol. 16(9), pages 1-33, September.

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