Researchers at the Icahn School of Medicine at Mount Sinai report that regulation of a single, specific gene in a brain region related to drug addiction and depression is sufficient to reduce drug and stress responses. They published their epigenetic study (“Locus-specific epigenetic remodeling controls addiction- and depression-related behaviors”) in Nature Neuroscience.

Previous research has found links between epigenetic regulation and the diseases of drug addiction and depression in both human patients and animal models. Such regulation derives, in part, from the function of transcription factors, specialized proteins that bind to specific DNA sequences and either encourage or shut down the expression of a given gene.

Using mouse models of human depression, stress, and addiction, the current research team introduced synthetic-transcription factors into the brain in the nucleus accumbens at a single gene called FosB, which has been linked by past studies to both addiction and depression. They found that changes to this single gene brought on by the transcription factors made the study mice more resilient to stress and less likely to become addicted to cocaine.

“We found that histone methylation or acetylation at the Fosb locus in nucleus accumbens, a brain reward region, was sufficient to control drug- and stress-evoked transcriptional and behavioral responses via interactions with the endogenous transcriptional machinery,” wrote the investigators. “This approach allowed us to relate the epigenetic landscape at a given gene directly to regulation of its expression and to its subsequent effects on reward behavior.”

“Earlier work in our laboratory found that several transcription factors and downstream epigenetic modifications are altered by exposure to drugs or to stress and that these changes, in turn, control gene expression,” says Eric J. Nestler, M.D., Ph.D., Nash Family Professor, Chair of the Department of Neuroscience and Director of the Friedman Brain Institute at the Icahn School of Medicine at Mount Sinai, who led the study. “But because such epigenetic regulation occurs at hundreds or thousands of genes, until now it had been impossible to determine the difference between the mere presence of an epigenetic modification and its functional relevance to neuropsychiatric disease.”

Expression of the FosB gene in nerve cells is both necessary and sufficient for drug and stress responsiveness in mice. In particular, activation of FosB expression is linked to increased sensitivity to drugs and to resilience to stress, and is altered by exposure to such stimuli in the brains of mouse models and in drug-addicted and depressed human patients.

“While drug addiction and depression are hereditary diseases that regulate gene expression in the brain, the field has yet to uncover relevant mutations in gene sequence that underlie these disorders,” explains Elizabeth A Heller, Ph.D., lead author on the paper. “Therefore, we focused on changes in gene structure to probe the mechanism of action of such changes in drug and stress sensitivity. Our data is a critical first step toward developing novel therapeutics to combat these neuropsychiatric diseases. In addition, the use of engineered transcription factors has broad implications outside of neuroscience because epigenetic gene regulation underlies many diseases, including most forms of cancer.”








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