NEW YORK, NY — November 12, 2026— Researchers at the New York Genome Center (NYGC) and collaborating institutions have developed complementary maps of gene regulation in the human brain that reveal how complex regulatory programs help establish and maintain the identities of different brain cells.
Published in Cell , the two studies profile more than 1.3 million brain nuclei. One focuses on eight regions of the basal ganglia; the other examines 18 cortical, cerebellar, and pontine regions. Together, they help explain how cells with essentially the same DNA sequence acquire distinct molecular identities and provide resources for investigating how genetic variation may affect those identities.
Both human studies are part of the National Institutes of Health BRAIN Initiative Cell Atlas Network (BICAN), a collaborative effort to map the brain's diverse cell types. By comparing gene regulation across human brain cell types, these studies help explain the molecular programs underlying cellular identity and provide a reference for investigating their disruption in brain disorders.
"To understand what makes a brain cell distinct, we need to study both the genes it uses and the genes it keeps silent," said Bing Ren, PhD, senior author and CEO and Scientific Director of the New York Genome Center . "These studies bring those two sides of gene regulation into view and give us a foundation for investigating how genetic variation may affect particular brain cell types."
Mapping the Regulatory Programs of Basal Ganglia Neurons
The basal ganglia play important roles in movement, learning, emotion, cognition, and reward. The first study, "Single-cell analysis of chromatin state and transcriptome in the human basal ganglia," analyzed more than 608,000 cells from eight regions of the basal ganglia in neurotypical human donors, identifying active and repressive chromatin states across 61 cell groups, and their dysfunction has been associated with disorders including Parkinson's disease, Huntington's disease, schizophrenia, and addiction.
The researchers used Droplet Paired-Tag, a method that jointly measures gene expression and histone modifications in individual nuclei. Histones are proteins around which DNA is packaged; chemical modifications to these proteins help distinguish regions associated with gene activity or repression. Across the study's profiles, the team measured H3K27ac, associated with active regulatory regions, and H3K27me3 and H3K9me3, two histone marks associated with gene repression.
The team identified distinct combinations of homeobox transcription factors —proteins that regulate gene activity— across neuronal populations. These combinations were associated with characteristic patterns of gene expression and chromatin state, supporting a model in which a homeobox "code" contributes to neuronal identity.
"The idea that combinations of homeobox factors help define neuronal identity emerged from studies in the worm C. elegans and has gained support in other species," said Lei Chang, Ph.D., postdoctoral research associate in the Ren lab and the leading author of this study. "Finding related patterns in human basal ganglia neurons supports the possibility that this organizing principle extends to the human brain."
Repressive Chromatin Preserves Clues to Developmental History
The second study expands the view across the adult human brain, jointly profiling gene expression with either H3K27ac or H3K27me3 across more than 750,000 nuclei from 18 brain regions. The resulting multimodal atlas provides a detailed view of how genes are regulated across different brain cell types, distinguishing active and repressive regulatory states across diverse neuronal and glial populations.
Repressive chromatin carried information about the developmental history and spatial organization of brain cells. Glial cells retained molecular signatures associated with their forebrain or hindbrain origins, while cortical neurons showed regional patterns of gene activity. Repressive patterns in different classes of cortical neurons were also consistent with their developmental trajectories as they migrated to their final positions in the brain.
The study also identified a class of chromatin interactions, spanning exceptionally long distances, that were specific to mature neurons and associated with Polycomb-mediated repression. These interactions involve genes important during early development and may contribute to the long-term stabilization of neuronal identity after neurons have reached their mature state.
"The adult brain retains molecular traces of how its cells developed and reached their final locations," said Yang Xie, Ph.D., postdoctoral research associate in the Ren lab and the leading author of this study. "By examining repressive chromatin, we can see features of that history that gene expression alone may not reveal."
Using EpiBRAIN to Investigate Noncoding Genetic Variation
Many genetic variants associated with neurological and psychiatric traits lie outside protein-coding genes. Understanding their effects requires identifying the regulatory elements, genes, and cell types they may influence. The studies mapped cell-type-specific relationships between regulatory elements and gene promoters, helping researchers nominate candidate genes and regulatory networks for further investigation. Utilizing datasets from both studies, the researchers developed EpiBRAIN, a deep-learning model that uses sequence information and the regulatory atlas to predict the effects of genetic variation on epigenetic states and gene expression in specific brain cell types.
In the study's reported benchmarking tests, EpiBRAIN outperformed two leading models, Borzoi and AlphaGenome, at identifying genetic variants likely to influence gene expression in the basal ganglia, particularly for variants located far away from the genes. In a separate analysis, variants prioritized using its cell-type-specific predictions accounted for a larger estimated share of schizophrenia genetic heritability than those prioritized by Borzoi.
"EpiBRAIN helps us prioritize genetic changes that may affect gene regulation in particular brain cell types," said Guojie Zhong, Ph.D., postdoctoral research associate in the Ren lab and the developer of EpiBRAIN. "That gives us specific hypotheses to test experimentally about how noncoding variation may contribute to disease risk."
A Foundation for Further Research
The atlases and models provide a framework for tracing possible links from a disease-associated variant to a regulatory element, a candidate target gene, and a relevant brain cell type. Establishing those links will require experiments to test the predicted regulatory effects and their consequences for cell function.
The maps may also guide future studies of whether selected regulatory elements or chromatin states can be manipulated in particular cell types.
Publication and Resources
Paper: "Single-cell analysis of chromatin state and transcriptome in the human basal ganglia" published in Cell.'
Paper: "Single-cell multimodal atlas reveals regulatory programs in the human brain" published in Cell.
Open Resources for the Research Community
The datasets can be explored through two interactive resources that allow researchers to examine gene regulatory features across the profiled cell populations:
Human Basal Ganglia Epigenome Atlas:
https://basalganglia.epigenomes.net/
Human Brain Epigenome Atlas:
https://miniatlas.nygenome.org/
About the New York Genome Center
The NYGC is an independent, nonprofit academic research institution at the forefront of transforming biomedical research and clinical care. Founded as a collaborative venture by the region's premier academic, medical, and industry leaders, the NYGC aims to accelerate the translation of genomic research into new diagnostics, therapeutics, and treatments for human disease. NYGC member organizations and partners are united in an unprecedented collaboration of technology, science, and medicine that is designed to harness the power of innovation and discoveries to advance medical genomics and precision medicine and to benefit patients around the world.
Our institutional founding members include Cold Spring Harbor Laboratory, Columbia University, Memorial Sloan Kettering Cancer Center, NewYork-Presbyterian Hospital, New York University, Northwell Health, The Rockefeller University, and Weill Cornell Medicine. Our associate members include the American Museum of Natural History and the Hospital for Special Surgery.
Learn more at nygenome.org
