Massively parallel reporter assays and mouse transgenic assays provide correlated and complementary information about neuronal enhancer activity
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.
Authors
- Riana D. Hunter (ORCID: https://orcid.org/0000-0002-2888-1079)
- Pia Keukeleire (ORCID: https://orcid.org/0000-0002-8828-636X)
- Dianne Laboy Cintrón (ORCID: https://orcid.org/0000-0002-9785-3565)
- L Pennacchio (ORCID: https://orcid.org/0000-0002-8748-3732)
- Erik Beckman
- Sarah Barton (ORCID: https://orcid.org/0000-0001-7077-0906)
- Catherine S. Novak
- Kianna von Maydell
- Stephan Sanders (ORCID: https://orcid.org/0000-0001-9112-5148)
- Michael Kosicki (ORCID: https://orcid.org/0000-0001-7173-8852)
- Ilias Georgakopoulos‐Soares (ORCID: https://orcid.org/0000-0003-3641-1488)
- Ingrid Plajzer-Frick
- Max Schubach (ORCID: https://orcid.org/0000-0002-2032-6679)
- Jennifer A. Akiyama (ORCID: https://orcid.org/0000-0002-0667-9355)
- Momoe Kato (ORCID: https://orcid.org/0000-0002-1161-5233)
- Martin Kircher (ORCID: https://orcid.org/0000-0001-9278-5471)
- Nadav Ahituv (ORCID: https://orcid.org/0000-0002-7434-8144)
- Nicholas F. Page (ORCID: https://orcid.org/0000-0001-7173-5408)
- Patrick Godfrey
Institutions
- Pennsylvania State University (US)
- Lawrence Berkeley National Laboratory (US)
- University of California, San Francisco (US)
- University of Oxford (GB)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- University of Lübeck (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-23
- DOI
- https://doi.org/10.1038/s41467-025-60064-1
- Citations
- 12
- Primary Topic
- Genomics and Chromatin Dynamics
- Type
- article
- Field-Weighted Citation Impact
- 9.67
Funders
- U.S. Department of Energy
- National Institute of Mental Health
- National Human Genome Research Institute
- National Institute of Child Health and Human Development
- Lawrence Berkeley National Laboratory