Schizophrenia is a severe neuropsychiatric disorder characterized by hallucinations, false beliefs about oneself or the world (i.e., delusions), and other disruptions in thought, emotion and perception. Recent genetic studies show that many risk variants for this disorder lie in noncoding regions of the genome—stretches of DNA that do not alter protein sequences but regulate how genes are switched on and off.

One key way these noncoding variants influence gene regulation is by altering chromatin accessibility, the degree to which DNA is packaged tightly or loosely, which determines whether genes can be turned on or off. Chromatin accessibility is an epigenetic mark, meaning it affects gene activity without changing the underlying DNA sequence itself.

Researchers at the Center for Disease Neurogenomics, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai and other institutes in the United States recently mapped chromatin accessibility in neurons and other non-neuron cells from over one thousand brain samples from individuals with and without schizophrenia. By comparing these chromatin landscapes, they identified regulatory “switches” that differ between cases and controls. Their paper, published in Nature Neuroscience, reveals that many of these alterations trace back to early fetal brain development.

“Our work began with a longstanding question in psychiatry and neuroscience: why do genetic risk factors for schizophrenia, many of which act during early brain development—manifest clinically much later in life?” said Kiran Girdhar and Panos Roussos.

To explore this, our approach was to map chromatin accessibility, an epigenetic mark that reflects how open or closed DNA regions are, from adult brains with schizophrenia to see if we could find molecular ‘fingerprints’ of these early developmental disruptions.

The researchers analyzed postmortem brain tissue from the prefrontal cortex—a brain region consistently implicated in schizophrenia and critical for higher-order cognitive functions. They collected samples from individuals with schizophrenia and from healthy controls.

They separated nuclei into neuronal and non-neuronal fractions, allowing them to examine each cell type independently. The team then applied ATAC-seq (Assay for Transposase- Accessible Chromatin using sequencing), a cutting-edge technique that identifies regions of open chromatin by inserting molecular “tags” into accessible DNA. These tags mark which genomic regions are open and potentially active in each cell type, creating a detailed map of the regulatory landscape in over 1,300 brain samples, one of the largest studies of its kind.

Neuronal chromatin changes link genetic risk to fetal development

The team’s analysis yielded a critical finding: neuronal regions with higher chromatin accessibility in schizophrenia, but not changes in non-neuronal cells, showed strong enrichment for genetic risk variants. This highlighted the importance of examining specific cell types rather than bulk brain tissue and demonstrated that increased chromatin openness in neurons is directly linked to the risk of schizophrenia.

By integrating these chromatin maps with genetic data and single-cell analyses, the researchers discovered that neuronal regions with higher chromatin accessibility in schizophrenia resembled chromatin patterns typically seen in fetal brain development. This suggested that molecular signatures established early in life persist into adulthood and contribute to disease risk.

The team also identified a prominent neuronal trans-regulatory domain, a coordinated network of genomic regions that communicate across chromosomes to control gene activity together. Unlike typical gene regulation where control elements sit adjacent to the genes they affect, a trans-regulatory domain acts as a genomic “hub” that orchestrates activity across distant locations. This hub was particularly enriched in immature glutamatergic neurons and consolidated the key neurodevelopmental chromatin signatures seen in schizophrenia.

“The chromatin patterns we observed in adult neurons with schizophrenia mirror those found in the developing fetal brain,” explained Girdhar and Roussos. “This provides a molecular bridge between early developmental processes and the adult disease state.”

To validate these findings, the team tested whether genetic risk variants within this trans-regulatory domain could predict disease. Remarkably, despite representing only 2–3% of all known schizophrenia risk variants, these specific variants within the regions of higher chromatin accessibility reliably distinguished individuals with schizophrenia from those without it in an independent cohort of over 195,000 individuals from the Million Veteran Program.

Directions for future research

“This study provides one of the most detailed maps to date of neuronal and non-neuronal chromatin accessibility map in the context of schizophrenia,” said Girdhar and Roussos. “It shows that the molecular architecture of the disease is deeply rooted in early brain development, even though symptoms appear much later.”

Looking ahead, the team aims to move beyond studying all neurons together, to instead pinpoint specific neuronal subtypes and cortical layers that show the strongest disease-linked chromatin changes. By integrating single-cell ATAC-seq with spatial mapping, they hope to localize these regulatory signals within brain tissue and connect them with single-cell RNA and protein data.

This integrative approach will reveal which genes and proteins are controlled by open chromatin regions in each neuronal layer. Ultimately, their goal is to create a comprehensive, cell-type–specific map of schizophrenia risk that can guide the discovery of precise therapeutic targets for the disorder.

© 2025 Science X Network