Researchers have created a comprehensive map of gene regulation across the adult mouse brain, revealing how different epigenomic mechanisms contribute to the remarkable diversity of brain cells. Published in Cell , the study integrates gene expression with multiple layers of epigenomic information in millions of individual nuclei, providing new insights into how brain cell identities are established and maintained.
Previous large-scale brain atlases have identified numerous cell types and characterized the genes they express. However, less is known about the molecular mechanisms that control these gene expression programs. The new study addresses this challenge by systematically mapping active and repressive chromatin states across the brain, revealing distinct roles for different regulatory mechanisms and improving the identification of DNA elements that control gene activity.
Led by researchers from the laboratory of Bing Ren, PhD, now at the New York Genome Center and Columbia University, in collaboration with scientists at the University of California, San Diego, the Salk Institute for Biological Studies, Washington University in St. Louis, and other institutions, the study used advanced single-cell technologies to build an integrated reference of the brain's regulatory genome. The resulting resource provides a foundation for studying how genetic variation and epigenomic regulation contribute to brain function and neurological disease.
Although previous studies have mapped brain cell types and their gene expression profiles in considerable detail, understanding how those cells acquire and maintain their distinct identities requires examining the molecular mechanisms that control gene activity. By bringing these complementary layers of information together, the new atlas provides a framework for investigating how genes are activated or repressed in different cell populations.
"The brain contains an extraordinary diversity of cell types, all sharing essentially the same genome. A fundamental question is how each cell type establishes and maintains its distinct identity. Our study goes beyond cataloging brain cells to reveal the regulatory mechanisms that control their gene expression programs. This atlas provides a foundation for understanding brain development, function, and disease," said Bing Ren, PhD, CEO and Scientific Director of the New York Genome Center and a senior author of the study.
"This new, detailed understanding of how cell types in different brain regions regulate their gene expression will enable cell-specific approaches to neuroscience discovery and innovation that were previously impossible," said Margarita Behrens, PhD , a research professor at the Salk Institute and co-corresponding author of the study.
A More Detailed View of the Brain's Regulatory Genome
The mammalian brain contains an extraordinary diversity of neurons and other cell types, each with specialized functions. Although these cells share essentially the same DNA sequence, they express different sets of genes. Understanding how these distinct gene expression programs are established and maintained is a fundamental challenge in neuroscience.
Previous large-scale brain atlases have identified numerous cell types based on their gene expression patterns and chromatin accessibility. However, these measurements provide only a partial picture of how genes are regulated. Other epigenomic features, including histone modifications, DNA methylation, and three-dimensional genome organization, play important roles in controlling gene activity.
Using Paired-Tag, a single-cell technology developed in the Ren laboratory that simultaneously measures gene expression and histone modifications, researchers characterized the epigenomic landscape of the adult mouse brain. They then integrated these measurements with existing genomic datasets to build a unified atlas covering more than 100 neuronal and non-neuronal cell subclasses.
The analysis identified distinct chromatin states associated with active, primed, and repressed regions of the genome. Across the profiled cell subclasses, the researchers were able to assign a chromatin state to approximately 81% of the genome, substantially expanding the regulatory information available beyond annotations based on chromatin accessibility alone.
One important discovery was that different forms of repressive chromatin contribute to brain cell identity in distinct ways. The histone modification H3K27me3, associated with Polycomb-mediated repression, helps distinguish closely related cell populations, whereas H3K9me3 is associated with broader patterns of cellular identity. These findings reveal how different mechanisms of gene repression contribute to the remarkable diversity of brain cells. The study also showed that integrating histone modifications with chromatin accessibility improves the identification of candidate enhancers—regions of noncoding DNA that control when and where genes are expressed. This provides a more refined approach to identifying regulatory elements that help establish and maintain cell-type-specific gene expression programs.
From Mapping Gene Regulation to Predicting Its Function
Beyond creating a comprehensive reference atlas, the study provides new tools for understanding how DNA sequence determines gene regulatory activity.
The researchers developed deep-learning models that use DNA sequence to predict cell-type-specific epigenomic features and gene expression. By learning relationships between DNA sequences and regulatory patterns across different brain cell populations, these models offer a computational framework for investigating the regulatory information encoded in the genome.
This is particularly important for understanding the effects of genetic variation. Many genetic variants associated with neurological and psychiatric disorders occur in noncoding regions of the genome, making it difficult to determine how they influence disease risk. The new atlas and computational models provide resources for identifying regulatory elements and generating hypotheses about how genetic variants may alter gene activity in specific brain cell types.
Because the mouse is a widely used experimental model for studying brain development, function, and disease, these resources could also guide future experiments to investigate the molecular mechanisms underlying neurological disorders.
An Open Resource for the Neuroscience Community
To make these findings broadly accessible, the researchers have made the epigenomic atlas available through the CATlas online portal. The resource allows scientists to explore gene expression, histone modifications, chromatin states, and other regulatory features across the profiled brain cell types.
By bringing together multiple layers of genomic information, the atlas offers a reference for investigating how gene regulatory programs differ among brain cell types and how they may be altered during development, aging, and disease.
The study also complements two additional human brain epigenomic atlas studies from the Ren laboratory appearing in the same issue of Cell. Together, the three publications represent a major advance in understanding the gene regulatory architecture of the mammalian brain, providing complementary resources for studying the human brain and its widely used experimental mouse model.
Publication and Resources
Paper: "An Integrative Single-Cell Epigenomic Atlas Annotates the Regulatory Genome of the Adult Mouse Brain," published in Cell.
Atlas resource: Adult Mouse Brain Paired-Tag CATlas
About the New York Genome Center
The New York Genome Center (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, 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 designed to harness innovation and discovery to advance medical genomics and precision medicine and benefit patients around the world.
NYGC's 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. Associate members include the American Museum of Natural History and the Hospital for Special Surgery.
Learn more at nygenome.org .
