Single-cell Multiome Analysis of Chromatin State and Transcriptome in the Human Basal Ganglia
Year: 2026
Type: preprint
Abstract: SUMMARY 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 cis -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. HIGHLIGHTS Joint single-cell profiling of transcriptomes and three histone modifications across eight human basal ganglia regions characterizes active and repressive chromatin states at cell-type resolution. Cell-type-specific gene regulatory programs decode combinatorial homeobox TF grammar governing the identity and diversification of basal ganglia neurons. Intergrative analyses link noncoding neuropsychiatric risk variants to specific cell types, regulatory elements, and candidate target genes. A sequence-to-function deep-learning model predicts gene regulation from DNA sequence and prioritizes functional disease-associated variants.
Authors: Lei Chang, Kai Li, Yang Xie, Guojie Zhong, Jonathan A. Rink, Cindy Tatiana Báez-Becerra, Audrey Lie, Hannah S Indralingam, Keyi Dong, Timothy Loe, Zhaoning Wang, Songpeng Zu, Joseph Colin Kern, Zoey Zhao, Eric Boone, Jesus Flores, Alexander Monell, Jacqueline Olness, Cesar Barragan, Emma Osgood, William Owens, Natalie Schenker-Ahmed, Wenjin Zhang, Di Liu, Ariana S. Barcoma, Jackson K. Willier, Kyle W. Knutson, Kaitlyn G. Russo, Jiayi Liu, Silvia Cho, Jessica Arzavala, Carissa K. Young, Guha V. Sundaram, Austin C. Manning, Yareli Sanchez, Aleksandra Bikkina, Jillian Berry, Xiaomeng Gao, Carolyn O’Connor, Michelle Liem, Mikayla V. Marrin, Cynthia Rose, Shane N. Alt, Chenxu Zhu, Nathan R Zemke, Wubin Ding, Amit Klein, Yuanyuan Fu, Nelson Johansen, Trygve E. Bakken, Rebecca D. Hodge, C. Dirk Keene, Ed S. Lein, Daofeng Li, Quan Zhu, Ting Wang, Xiangmin Xu, Joseph R. Ecker, M. Margarita Behrens, Bing Ren
Institutions: University of California San Diego, New York Genome Center, Salk Institute for Biological Studies, Washington University in St. Louis, Columbia University Irving Medical Center, University of California, Irvine, Weill Cornell Medicine, Allen Institute for Brain Science, University of Washington, Howard Hughes Medical Institute, Moores Cancer Center, Columbia University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7127600604