Multiomic single-cell profiling identifies critical regulators of postnatal brain

Tereza Clarence; Jaroslav Bendl; Xuan Cao; Xinyi Wang; Shiwei Zheng; Gabriel E. Hoffman; Alexey Kozlenkov; Aram Hong; Marina Iskhakova; Manoj K. Jaiswal; Sarah Murphy; Alexander Yu; Vahram Haroutunian; Stella Dracheva; Schahram Akbarian; John F. Fullard; Guo Cheng Yuan; Donghoon Lee; Panos Roussos

doi:10.1038/s41588-025-02083-8

Multiomic single-cell profiling identifies critical regulators of postnatal brain

Tereza Clarence, Jaroslav Bendl, Xuan Cao, Xinyi Wang, Shiwei Zheng, Gabriel E. Hoffman, Alexey Kozlenkov, Aram Hong, Marina Iskhakova, Manoj K. Jaiswal, Sarah Murphy, Alexander Yu, Vahram Haroutunian, Stella Dracheva, Schahram Akbarian, John F. Fullard, Guo Cheng Yuan, Donghoon Lee, Panos Roussos

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Abstract

Human brain development spans from embryogenesis to adulthood, with dynamic gene expression controlled by cell-type-specific cis-regulatory element activity and three-dimensional genome organization. To advance our understanding of postnatal brain development, we simultaneously profiled gene expression and chromatin accessibility in 101,924 single nuclei from four brain regions across ten donors, covering five key postnatal stages from infancy to late adulthood. Using this dataset and chromosome conformation capture data, we constructed enhancer-based gene regulatory networks to identify cell-type-specific regulators of brain development and interpret genome-wide association study loci for ten main brain disorders. Our analysis connected 2,318 cell-specific loci to 1,149 unique genes, representing 41% of loci linked to the investigated traits, and highlighted 55 genes influencing several disease phenotypes. Pseudotime analysis revealed distinct stages of postnatal oligodendrogenesis and their regulatory programs. These findings provide a comprehensive dataset of cell-type-specific gene regulation at critical timepoints in postnatal brain development.

Original language	English
Article number	5581
Pages (from-to)	591-603
Number of pages	13
Journal	Nature Genetics
Volume	57
Issue number	3
DOIs	https://doi.org/10.1038/s41588-025-02083-8
State	Published - Mar 2025

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Clarence, T., Bendl, J., Cao, X., Wang, X., Zheng, S., Hoffman, G. E., Kozlenkov, A., Hong, A., Iskhakova, M., Jaiswal, M. K., Murphy, S., Yu, A., Haroutunian, V., Dracheva, S., Akbarian, S., Fullard, J. F., Yuan, G. C., Lee, D., & Roussos, P. (2025). Multiomic single-cell profiling identifies critical regulators of postnatal brain. Nature Genetics, 57(3), 591-603. Article 5581. https://doi.org/10.1038/s41588-025-02083-8

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title = "Multiomic single-cell profiling identifies critical regulators of postnatal brain",

abstract = "Human brain development spans from embryogenesis to adulthood, with dynamic gene expression controlled by cell-type-specific cis-regulatory element activity and three-dimensional genome organization. To advance our understanding of postnatal brain development, we simultaneously profiled gene expression and chromatin accessibility in 101,924 single nuclei from four brain regions across ten donors, covering five key postnatal stages from infancy to late adulthood. Using this dataset and chromosome conformation capture data, we constructed enhancer-based gene regulatory networks to identify cell-type-specific regulators of brain development and interpret genome-wide association study loci for ten main brain disorders. Our analysis connected 2,318 cell-specific loci to 1,149 unique genes, representing 41% of loci linked to the investigated traits, and highlighted 55 genes influencing several disease phenotypes. Pseudotime analysis revealed distinct stages of postnatal oligodendrogenesis and their regulatory programs. These findings provide a comprehensive dataset of cell-type-specific gene regulation at critical timepoints in postnatal brain development.",

author = "Tereza Clarence and Jaroslav Bendl and Xuan Cao and Xinyi Wang and Shiwei Zheng and Hoffman, {Gabriel E.} and Alexey Kozlenkov and Aram Hong and Marina Iskhakova and Jaiswal, {Manoj K.} and Sarah Murphy and Alexander Yu and Vahram Haroutunian and Stella Dracheva and Schahram Akbarian and Fullard, {John F.} and Yuan, {Guo Cheng} and Donghoon Lee and Panos Roussos",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.",

year = "2025",

month = mar,

doi = "10.1038/s41588-025-02083-8",

language = "English",

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Clarence, T, Bendl, J, Cao, X, Wang, X, Zheng, S, Hoffman, GE , Kozlenkov, A, Hong, A, Iskhakova, M, Jaiswal, MK, Murphy, S, Yu, A, Haroutunian, V, Dracheva, S, Akbarian, S , Fullard, JF , Yuan, GC , Lee, D & Roussos, P 2025, 'Multiomic single-cell profiling identifies critical regulators of postnatal brain', Nature Genetics, vol. 57, no. 3, 5581, pp. 591-603. https://doi.org/10.1038/s41588-025-02083-8

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AU - Clarence, Tereza

AU - Bendl, Jaroslav

AU - Cao, Xuan

AU - Wang, Xinyi

AU - Zheng, Shiwei

AU - Hoffman, Gabriel E.

AU - Kozlenkov, Alexey

AU - Hong, Aram

AU - Iskhakova, Marina

AU - Jaiswal, Manoj K.

AU - Murphy, Sarah

AU - Yu, Alexander

AU - Haroutunian, Vahram

AU - Dracheva, Stella

AU - Akbarian, Schahram

AU - Fullard, John F.

AU - Yuan, Guo Cheng

AU - Lee, Donghoon

AU - Roussos, Panos

PY - 2025/3

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N2 - Human brain development spans from embryogenesis to adulthood, with dynamic gene expression controlled by cell-type-specific cis-regulatory element activity and three-dimensional genome organization. To advance our understanding of postnatal brain development, we simultaneously profiled gene expression and chromatin accessibility in 101,924 single nuclei from four brain regions across ten donors, covering five key postnatal stages from infancy to late adulthood. Using this dataset and chromosome conformation capture data, we constructed enhancer-based gene regulatory networks to identify cell-type-specific regulators of brain development and interpret genome-wide association study loci for ten main brain disorders. Our analysis connected 2,318 cell-specific loci to 1,149 unique genes, representing 41% of loci linked to the investigated traits, and highlighted 55 genes influencing several disease phenotypes. Pseudotime analysis revealed distinct stages of postnatal oligodendrogenesis and their regulatory programs. These findings provide a comprehensive dataset of cell-type-specific gene regulation at critical timepoints in postnatal brain development.

AB - Human brain development spans from embryogenesis to adulthood, with dynamic gene expression controlled by cell-type-specific cis-regulatory element activity and three-dimensional genome organization. To advance our understanding of postnatal brain development, we simultaneously profiled gene expression and chromatin accessibility in 101,924 single nuclei from four brain regions across ten donors, covering five key postnatal stages from infancy to late adulthood. Using this dataset and chromosome conformation capture data, we constructed enhancer-based gene regulatory networks to identify cell-type-specific regulators of brain development and interpret genome-wide association study loci for ten main brain disorders. Our analysis connected 2,318 cell-specific loci to 1,149 unique genes, representing 41% of loci linked to the investigated traits, and highlighted 55 genes influencing several disease phenotypes. Pseudotime analysis revealed distinct stages of postnatal oligodendrogenesis and their regulatory programs. These findings provide a comprehensive dataset of cell-type-specific gene regulation at critical timepoints in postnatal brain development.

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Multiomic single-cell profiling identifies critical regulators of postnatal brain

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