Single-cell Multiome Analysis of Chromatin State and Transcriptome in the Human Basal Ganglia
The basal ganglia play essential roles in motor control, emotion, learning and reward processing. Their dysfunction contributes to many neurological and psychiatric disorders. However, the gene regulatory programs defining basal ganglia cell-type identity and function remain poorly understood, limiting interpretation of disease-associated non-coding variants. Here, we present the first single-cell multiome atlas of histone modifications and transcriptomes across eight basal ganglia regions from neurotypical adult human donors. Joint profiling reveals cell-type-specific deployment of active and repressive <i>cis</i>-regulatory elements and gene regulatory networks, and suggests a combinatorial homeobox transcription factor code underlying cell identity. Integration with matched spatial transcriptomic MERFISH data uncovers regional heterogeneity of epigenomic landscapes. Comparative analysis between human and mouse medium spiny neurons uncovers conservation of core gene regulatory features. This atlas interprets non-coding risk variants of neuropsychiatric disorders and supports the development of a deep learning model to predict gene regulation and functional effects of disease-associated variants.
Authors
- Alexander Monell (ORCID: https://orcid.org/0000-0002-5399-2205)
- Jan F Kern (ORCID: https://orcid.org/0000-0002-7272-1603)
- Nelson Johansen (ORCID: https://orcid.org/0000-0002-4436-969X)
- Nathan R. Zemke (ORCID: https://orcid.org/0000-0002-6326-5925)
- Anita Lie
- Songpeng Zu (ORCID: https://orcid.org/0000-0001-9753-5623)
- Guojie Zhong (ORCID: https://orcid.org/0000-0001-5664-9069)
- Jessica Arzavala
- Michelle Liem (ORCID: https://orcid.org/0009-0004-0542-7166)
- Silvia Cho (ORCID: https://orcid.org/0009-0002-0967-4469)
- Chenxu Zhu (ORCID: https://orcid.org/0000-0003-4216-6562)
- Carissa Young
- Daofeng Li (ORCID: https://orcid.org/0000-0003-4851-2163)
- Natalie M. Schenker-Ahmed (ORCID: https://orcid.org/0000-0002-2651-1576)
- Cindy Tatiana Báez-Becerra
- William S. Owens
- Zoey Zhao (ORCID: https://orcid.org/0009-0005-3822-7985)
- X Xu
- Hannah S. Indralingam (ORCID: https://orcid.org/0009-0000-1790-109X)
- Di Liu (ORCID: https://orcid.org/0000-0002-1180-5248)
- Lei Chang (ORCID: https://orcid.org/0000-0002-4508-3853)
- Keyi Dong
- Yuanyuan Fu (ORCID: https://orcid.org/0000-0001-5934-6573)
- Quan Zhu
- Wenjin Zhang (ORCID: https://orcid.org/0000-0002-5979-0102)
- Jackson Willier
- Ariana Barcoma
- Timothy Loe
- Mikayla Marrin
- Amit Klein
- Zhaoning Wang
- Kai Li
- Yang Xie
- Aleksandra Bikkina
- Kaitlyn G. Russo
- Carolyn OConnor
- Shane N. Alt
- Yareli Sanchez
- Cynthia Rose
- Jesus Flores
- Kyle W. Knutson
- Eric Boone
- Wubin Ding
- M. Margarita Behrens
- Ting Wang
- Cesar Barragan
- Jacqueline Olness
- Jonathan A. Rink
- Xiaomeng Gao
- Joseph R. Ecker
- Emma Osgood
- Rebecca D. Hodge
- Bing Ren
- C. Dirk Keene
- Ed S. Lein
- Trygve E. Bakken
- Austin C. Manning
- Guha V. Sundaram
Institutions
- Salk Institute for Biological Studies (US)
- Allen Institute for Brain Science (US)
- Howard Hughes Medical Institute (US)
- University of Washington (US)
- University of California, Irvine (US)
- Cornell University (US)
- Columbia University Irving Medical Center (US)
- University of California San Diego (US)
- Allen Institute (US)
- New York Genome Center (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-02-04
- DOI
- https://doi.org/10.64898/2026.02.03.703645
- Citations
- 1
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 22.24
Funders
- Life Sciences Research Foundation
- Broad Institute
- National Institutes of Health
- National Cancer Institute