A map of enhancer regions in primary human neural progenitor cells using capture STARR-seq
- Sophia C. Gaynor-Gillett1,15,
- Lijun Cheng2,15,
- Manman Shi2,
- Jason Liu3,
- Gaoyuan Wang3,
- Megan Spector2,
- Qiuyu Guo4,
- Le Qi5,
- Mary Flaherty2,
- Martha Wall2,
- Ahyeon Hwang6,
- Mengting Gu3,
- Zhanlin Chen3,
- Yuhang Chen3,
- PsychENCODE Consortium16,
- Jennifer R. Moran2,
- Jing Zhang6,
- Donghoon Lee7,8,
- Mark Gerstein3,9,10,11,
- Daniel Geschwind5,12,13 and
- Kevin P. White14
- 1Department of Biology, Cornell College, Mount Vernon, Iowa 52314, USA;
- 2Tempus Labs, Inc., Chicago, Illinois 60654, USA;
- 3Computational Biology and Bioinformatics Program, Yale University, New Haven, Connecticut 06511, USA;
- 4Discovery Biomarkers, Amgen Research, Thousand Oaks, California 91320, USA;
- 5Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA;
- 6Department of Computer Science, University of California Irvine, Irvine, California 92697, USA;
- 7Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
- 8Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
- 9Department of Statistics and Data Science, Yale University, New Haven, Connecticut 06511, USA;
- 10Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06511, USA;
- 11Department of Computer Science, Yale University, New Haven, Connecticut 06511, USA;
- 12Department of Psychiatry and Semel Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA;
- 13Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA;
- 14Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
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↵15 These authors contributed equally to this work.
Abstract
Genome-wide association studies (GWASs) and expression analyses implicate noncoding regulatory regions as harboring risk factors for psychiatric disease, but functional characterization of these regions remains limited. Here, we perform capture STARR-sequencing of over 70,000 candidate regions to identify active enhancers in primary human neural progenitor cells (phNPCs). We select candidate regions by integrating data from NPCs, prefrontal cortex, developmental timepoints, and GWASs. Over 8000 regions demonstrate enhancer activity in the phNPCs, and we link these regions to over 2200 predicted target genes. These genes are involved in neuronal and psychiatric disease-associated pathways, including neuronal system, nervous system development, and developmental delay. We functionally validate a subset of these enhancers using mutation STARR-sequencing and CRISPR deletions, demonstrating the effects of genetic variation on enhancer activity and enhancer deletion on gene expression. Overall, we identify thousands of highly active enhancers and functionally validated a subset of these enhancers, improving our understanding of regulatory networks underlying brain function and disease.
Footnotes
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↵16 Full consortium author list is available in the Supplemental Materials.
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.279584.124.
- Received May 16, 2024.
- Accepted June 4, 2025.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see https://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
