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Massively parallel reporter assays and mouse transgenic assays provide correlated and complementary information about neuronal enhancer activity

Author

Listed:
  • Michael Kosicki

    (Lawrence Berkeley National Laboratory)

  • Dianne Laboy Cintrón

    (University of California San Francisco
    University of California San Francisco)

  • Pia Keukeleire

    (University Medical Center Schleswig-Holstein, University of Lübeck)

  • Max Schubach

    (Berlin Institute of Health at Charité – Universitätsmedizin Berlin)

  • Nicholas F. Page

    (University of California San Francisco
    University of California San Francisco
    University of California, San Francisco)

  • Ilias Georgakopoulos-Soares

    (The Pennsylvania State University College of Medicine)

  • Jennifer A. Akiyama

    (Lawrence Berkeley National Laboratory)

  • Ingrid Plajzer-Frick

    (Lawrence Berkeley National Laboratory)

  • Catherine S. Novak

    (Lawrence Berkeley National Laboratory)

  • Momoe Kato

    (Lawrence Berkeley National Laboratory)

  • Riana D. Hunter

    (Lawrence Berkeley National Laboratory)

  • Kianna Maydell

    (Lawrence Berkeley National Laboratory)

  • Sarah Barton

    (Lawrence Berkeley National Laboratory)

  • Patrick Godfrey

    (Lawrence Berkeley National Laboratory)

  • Erik Beckman

    (Lawrence Berkeley National Laboratory)

  • Stephan J. Sanders

    (University of California San Francisco
    University of California, San Francisco
    University of Oxford)

  • Martin Kircher

    (University Medical Center Schleswig-Holstein, University of Lübeck
    Berlin Institute of Health at Charité – Universitätsmedizin Berlin)

  • Len A. Pennacchio

    (Lawrence Berkeley National Laboratory)

  • Nadav Ahituv

    (University of California San Francisco
    University of California San Francisco)

Abstract

High-throughput massively parallel reporter assays (MPRAs) and phenotype-rich in vivo transgenic mouse assays are two potentially complementary ways to study the impact of noncoding variants associated with psychiatric diseases. Here, we investigate the utility of combining these assays. Specifically, we carry out an MPRA in induced human neurons on over 50,000 sequences derived from fetal neuronal ATAC-seq datasets and enhancers validated in mouse assays. We also test the impact of over 20,000 variants, including synthetic mutations and 167 common variants associated with psychiatric disorders. We find a strong and specific correlation between MPRA and mouse neuronal enhancer activity. Four out of five tested variants with significant MPRA effects affected neuronal enhancer activity in mouse embryos. Mouse assays also reveal pleiotropic variant effects that could not be observed in MPRA. Our work provides a catalog of functional neuronal enhancers and variant effects and highlights the effectiveness of combining MPRAs and mouse transgenic assays.

Suggested Citation

  • Michael Kosicki & Dianne Laboy Cintrón & Pia Keukeleire & Max Schubach & Nicholas F. Page & Ilias Georgakopoulos-Soares & Jennifer A. Akiyama & Ingrid Plajzer-Frick & Catherine S. Novak & Momoe Kato &, 2025. "Massively parallel reporter assays and mouse transgenic assays provide correlated and complementary information about neuronal enhancer activity," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60064-1
    DOI: 10.1038/s41467-025-60064-1
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