Single-Cell Atlas of Transcription and Chromatin States Reveals Regulatory Programs in the Human Brain
Directly measuring chromatin states alongside transcription is essential for understanding how cell-type-specific regulatory programs are established and maintained in the adult human brain. We present a large-scale single-cell multimodal atlas generated by jointly profiling transcriptome with active (H3K27ac) and repressive (H3K27me3) histone modifications across 18 brain regions. We profile >750,000 nuclei spanning 160 cell types and integrate these data with chromatin accessibility, DNA methylation, 3D genome architecture, and spatial transcriptome. This framework annotates >500,000 regulatory elements and resolves cell-type-specific chromatin states. We link enhancers to target genes, infer gene regulatory networks, and classify chromatin interactions, revealing neuron-enriched long-range Polycomb repression of developmental genes. Integrating these maps with GWAS data and sequence-based model prioritizes noncoding variants, effector genes, and vulnerable cell types for neuropsychiatric disorders. Finally, cross-species comparisons show conserved activation but more divergent repression. Together, this study provides a functional reference for interpreting noncoding variants, epigenetic memory, and brain organization.
Authors
- Alexander Monell (ORCID: https://orcid.org/0000-0002-5399-2205)
- Jacinta Lucero (ORCID: https://orcid.org/0000-0001-7578-6624)
- Kai Li (ORCID: https://orcid.org/0000-0003-4898-2827)
- Anita Lie
- Julia Osteen (ORCID: https://orcid.org/0000-0001-7058-3297)
- 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)
- Siavash Moghadami (ORCID: https://orcid.org/0000-0003-1251-7384)
- Carissa Young
- Chumo Chen
- Daofeng Li (ORCID: https://orcid.org/0000-0003-4851-2163)
- Stella Maris Cao
- Natalie M. Schenker-Ahmed (ORCID: https://orcid.org/0000-0002-2651-1576)
- William S. Owens
- Zoey Zhao (ORCID: https://orcid.org/0009-0005-3822-7985)
- Hannah S. Indralingam (ORCID: https://orcid.org/0009-0000-1790-109X)
- Lei Chang (ORCID: https://orcid.org/0000-0002-4508-3853)
- Keyi Dong
- Quan Zhu
- Jackson Willier
- Ariana Barcoma
- Timothy Loe
- Mikayla Marrin
- Amit Klein
- Zhaoning Wang
- Chu-Yi Tai
- Colin Kern
- Yang Xie
- Aleksandra Bikkina
- Wubin Ding
- M. Margarita Behrens
- Kaitlyn G. Russo
- Ting Wang
- Bohan Huang
- Cesar Barragan
- Carolyn OConnor
- Jonathan A. Rink
- Joseph R. Ecker
- Shane N. Alt
- Bing Ren
- Ethan Armand
- Yareli Sanchez
- C. Dirk Keene
- Cynthia Rose
- Jacqueline Olness
- Jesus Flores
- Kyle W. Knutson
- Rebecca D. Hodge
- Tatiana Baez-Becerra
- Xiangming Xu
- Nora Emerson
- Eric Boone
Institutions
- James S. McDonnell Foundation (US)
- 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)
- Washington University in St. Louis (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
- 2026-02-03
- DOI
- https://doi.org/10.64898/2026.02.02.703166
- Citations
- 1
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 22.24