Massively parallel reporter assays and mouse transgenic assays provide correlated and complementary information about neuronal enhancer activity
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. Sp...
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60064-1 |
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| author | 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 Riana D. Hunter Kianna von Maydell Sarah Barton Patrick Godfrey Erik Beckman Stephan J. Sanders Martin Kircher Len A. Pennacchio Nadav Ahituv |
| author_facet | 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 Riana D. Hunter Kianna von Maydell Sarah Barton Patrick Godfrey Erik Beckman Stephan J. Sanders Martin Kircher Len A. Pennacchio Nadav Ahituv |
| author_sort | Michael Kosicki |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-8e3ee87d4e7a417fb6beb3ca59926f46 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-8e3ee87d4e7a417fb6beb3ca59926f462025-08-20T01:53:23ZengNature PortfolioNature Communications2041-17232025-05-0116111310.1038/s41467-025-60064-1Massively parallel reporter assays and mouse transgenic assays provide correlated and complementary information about neuronal enhancer activityMichael Kosicki0Dianne Laboy Cintrón1Pia Keukeleire2Max Schubach3Nicholas F. Page4Ilias Georgakopoulos-Soares5Jennifer A. Akiyama6Ingrid Plajzer-Frick7Catherine S. Novak8Momoe Kato9Riana D. Hunter10Kianna von Maydell11Sarah Barton12Patrick Godfrey13Erik Beckman14Stephan J. Sanders15Martin Kircher16Len A. Pennacchio17Nadav Ahituv18Environmental Genomics & Systems Biology Division, Lawrence Berkeley National LaboratoryDepartment of Bioengineering and Therapeutic Sciences, University of California San FranciscoInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of LübeckBerlin Institute of Health at Charité – Universitätsmedizin BerlinDepartment of Bioengineering and Therapeutic Sciences, University of California San FranciscoInstitute for Personalized Medicine, Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of MedicineEnvironmental Genomics & Systems Biology Division, Lawrence Berkeley National LaboratoryEnvironmental Genomics & Systems Biology Division, Lawrence Berkeley National LaboratoryEnvironmental Genomics & Systems Biology Division, Lawrence Berkeley National LaboratoryEnvironmental Genomics & Systems Biology Division, Lawrence Berkeley National LaboratoryEnvironmental Genomics & Systems Biology Division, Lawrence Berkeley National LaboratoryEnvironmental Genomics & Systems Biology Division, Lawrence Berkeley National LaboratoryEnvironmental Genomics & Systems Biology Division, Lawrence Berkeley National LaboratoryEnvironmental Genomics & Systems Biology Division, Lawrence Berkeley National LaboratoryEnvironmental Genomics & Systems Biology Division, Lawrence Berkeley National LaboratoryInstitute for Human Genetics, University of California San FranciscoInstitute of Human Genetics, University Medical Center Schleswig-Holstein, University of LübeckEnvironmental Genomics & Systems Biology Division, Lawrence Berkeley National LaboratoryDepartment of Bioengineering and Therapeutic Sciences, University of California San FranciscoAbstract 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.https://doi.org/10.1038/s41467-025-60064-1 |
| spellingShingle | 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 Riana D. Hunter Kianna von Maydell Sarah Barton Patrick Godfrey Erik Beckman Stephan J. Sanders Martin Kircher Len A. Pennacchio Nadav Ahituv Massively parallel reporter assays and mouse transgenic assays provide correlated and complementary information about neuronal enhancer activity Nature Communications |
| title | Massively parallel reporter assays and mouse transgenic assays provide correlated and complementary information about neuronal enhancer activity |
| title_full | Massively parallel reporter assays and mouse transgenic assays provide correlated and complementary information about neuronal enhancer activity |
| title_fullStr | Massively parallel reporter assays and mouse transgenic assays provide correlated and complementary information about neuronal enhancer activity |
| title_full_unstemmed | Massively parallel reporter assays and mouse transgenic assays provide correlated and complementary information about neuronal enhancer activity |
| title_short | Massively parallel reporter assays and mouse transgenic assays provide correlated and complementary information about neuronal enhancer activity |
| title_sort | massively parallel reporter assays and mouse transgenic assays provide correlated and complementary information about neuronal enhancer activity |
| url | https://doi.org/10.1038/s41467-025-60064-1 |
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