Abstract
Distinct regional functionality of the human cortex is orchestrated by diverse cellular and molecular processes, yet the underlying regulatory mechanisms remain poorly understood. We performed multiomic single-cell and spatial characterization of nine regions of the human cortex to define the gene regulatory networks and transcription factors that govern cell-type and region specificity. With the combined data of over three million cells, two striking patterns of cortical neuron specialization were uncovered: a rostral-caudal spatial pattern of calcium regulatory machinery, and subunit switching of multiple signaling receptor families across the transmodal-sensory axis. Gene regulatory network analysis revealed putative transcriptional regulators of cortical neuron specialization with cell-type- and region-specific gene regulation patterns. While regionalization was observed in gene expression, chromatin accessibility, and spatial distributions, these modalities exhibited distinct cortical patterns. Our findings illuminate critical neuronal pathways that vary throughout the cortex and the gene regulatory networks that establish cortical regionalization in the human brain.
Data availability
Data generated via SNARE-Seq2 can be found on the NEMO archive via the following link: https://data.nemoarchive.org/biccn/lab/zhang_kun/multimodal/sncell/ Associated metadata can be found in data S1. Data generated via DART-FISH is uploaded to the BIL archive and is freely accessible at the following https://doi.org/10.35077/g.1179. Source data are provided with this paper.
Code availability
Code used for this manuscript can be found at the following github repository56: https://github.com/ypauling/human_brain_atlas_cortex_regionality.
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Acknowledgements
We would like to thank the research brain donors and families who shared the precious brain materials used in these studies for their deep contributions to science. We would like to thank the University of Washington Biorepository and Integrated Neuropathology (BRaIN) Laboratory. We would like to thank the Snohomish, Pierce, and King County Medical Examiner offices for their collaboration and support of the Pacific Northwest Brain Donor Network. We would like to thank Lisa Keene, Aimee Schantz, Emily Ragaglia, and the staff of the BRaIN Lab for outstanding research coordination and technical support and Dr. William Romanow for his scientific and technical support. Figures 1A, 4A, 5A, and S11C were created with the help of Biorender.com. The work was supported by the following grants: National Institutes of Health grant U01MH114828-01A1 (K.Z., P.K., B.R., J.C.), National Institutes of Health grant R01 AG065541 (J.C.), National Institutes of Health grant R01 AG071465 (J.C.), National Institutes of Health grant P30 AG066509 (C.D.K.), National Institutes of Health grant U19 AG072458 (C.D.K.), National Institutes of Health grant U19 AG060909 (C.D.K.), Allen Institute of Brain Sciences (C.D.K.), Nancy and Buster Alvord Endowment (C.D.K.).
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Conceptualization: C.P., J.S., B.Y., C.J.C., N.Z., J.C., P.K., B.R., K.Z. Methodology: C.P., J.S., C.J.C., K.C., N.P., D.D., Q.H., Software: J.S., B.Y., C.J.C., Q.H., Formal Analysis: C.P., J.S., B.Y., C.J.C., Data Curation: J.S., B.Y., C.J.C., Investigation: C.P., J.S., C.J.C., K.C., N.P., D.D., H.I., A.H., C.S.L., J.K., Q.H., R.H. Visualization: C.P., J.S., B.Y., C.J.C., N.Z., L.R., A.S., Funding acquisition: K.Z., J.C., P.K., B.R., Project administration: C.P., J.S., N.Z., C.S.L., R.D.H., C.D.K., E.L., J.C., B.R., K.Z., Supervision: N.Z., P.K., J.C., B.R., K.Z. Writing – original draft: C.P., Writing – review & editing: C.P., J.S., B.Y., C.J.C., N.Z., C.S.L., L.R., A.S., P.K., J.C., B.R., K.Z.
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B.R. is a co-founder of Epigenome Technologies, and has equity in Arima Genomics. J.C. has an employment relationship with Neurocrine Biosciences Inc., a company that may potentially benefit from the research results. Dr. Chun’s relationship with Neurocrine Biosciences, Inc. has been reviewed and approved by Sanford Burnham Prebys Medical Discovery Institute in accordance with its Conflict of Interest Policies. The remaining authors declare no competing interests.
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Palmer, C.R., Song, J., Yang, B. et al. Single-cell multiomic human brain atlas reveals regulatory drivers of cortical regionality. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69368-2
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DOI: https://doi.org/10.1038/s41467-026-69368-2
