HMN 2026: how adult brain cells remember their origins

Researchers at Karolinska Institutet have created the first detailed map showing how genetic activity is controlled in individual cells of the adult human brain and spinal cord. The study, published in Nature Neuroscience, shows that oligodendroglia, the cells that form the brain’s insulating myelin, retain an “epigenetic memory” of developmental programs long after these genes are no longer active.

Inside every cell, DNA is tightly packed together with histone proteins. Whether a gene is turned on or off depends on how open this packaging is, and on chemical modifications to histones that can either promote or block gene activity.

In the new study, the researchers used advanced epigenomic technologies, including single-nucleus ATAC sequencing and a dual histone profiling method called nanoCUT&Tag, to analyze hundreds of thousands of individual cells from regions across the central nervous system.

Identified a previously unknown DNA region

“Having both chromatin accessibility and histone-level information at single?cell resolution helps understanding the logic of gene activation and repression in the adult human brain,” says corresponding author Professor Gonçalo Castelo-Branco at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet.

The map allowed the team to identify a previously unknown DNA region that helps regulate activity of Sox10, a key gene that defines the identity of oligodendrocytes.

The study also found that adult oligodendrocytes retain epigenetic marks at HOX gene clusters, genes crucial during early development, even though these genes are not active in mature cells.

“This ‘epigenetic memory’ of developmental states may allow adult oligodendrocytes to rapidly activate developmental genes when needed, for example during regeneration, but it may also make them more vulnerable to malignant transformation,” says Dr. Mukund Kabbe, first author of the study.

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