Serotonin Unexpectedly Regulates Expression of Brain Genes

Science Spotlight

The brain chemical serotonin can regulate expression of genes within neurons in a very unexpected way, as described in a NIDA-funded paper just published in the journal Nature. It is all part of the marvel of DNA and how it works to form our individual biological maps. The mechanism discovered may help us better understand a variety of brain disorders, including substance use and addiction.  

Image of a nucleosome, molecular model.
Image by ©iStock/Molekuul
Image of a nucleosome, molecular model.

Each of our cells contains two meters of DNA ─ the blueprint for all functions of all cells in our bodies. This DNA is wound around spools of histone proteins called nucleosomes. When the DNA encoding a specific gene is wound tightly within the spool, that gene is less likely to be expressed. When the gene is not wound as tightly, that gene is more likely to be expressed. This can affect many functions of a cell.

Serotonin is a chemical that can transmit signals between neurons in our brains and is involved in the regulation of mood. In fact, some antidepressant medications (SSRIs) alter the amounts of serotonin in the brain enabling mood changes. When small packages of serotonin are released from a neuron, the resulting signals set up a chain reaction of communication between different parts of the brain. 

Scientists discovered that a protein called Transglutaminase 2 can directly attach the chemical serotonin to the histone proteins ─ loosening the spool to enable more robust gene expression. Specifically, they found that in developing rodent brains and human neurons, genes near this serotonin modification are more likely to be expressed. They also discovered that a certain binding complex enables this process. 

The serendipitous discovery that the neurotransmitter serotonin can be chemically attached to histone proteins in the nucleus of cells and regulate gene expression raises more exciting questions to be answered. Does serotonin’s regulation of gene expression, in addition to serotonin neurotransmission, also play a role in the regulation of mood? Could this new knowledge be used to develop better medications to treat depression or other mood disorders in the future? How else might it affect the brain? Can a related neurotransmitter like dopamine, which plays an important role in substance use disorders, also be attached to histones to regulate gene expression in the brain? 

The research was done at the Icahn School of Medicine at Mount Sinai in New York City by Drs. Ian Maze (a 2016 NIDA Avenir Awardee) and Lorna Farrelly, a postdoctoral fellow in Dr. Maze’s lab). 

For a copy of the paper, published in Nature, go to: Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3.

To see NIH Director Dr. Francis Collins’ blog on this study, go to: Mood-Altering Messenger Goes Nuclear.

For more information on genetics and addiction, go to: DrugFacts: Genetics and Epigenetics of Addiction.

For more information, contact the NIDA press office at or 301-443-6245. Follow NIDA on Twitter and Facebook.

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About the National Institute on Drug Abuse (NIDA): NIDA is a component of the National Institutes of Health, U.S. Department of Health and Human Services. NIDA supports most of the world’s research on the health aspects of drug use and addiction. The Institute carries out a large variety of programs to inform policy, improve practice, and advance addiction science. For more information about NIDA and its programs, visit

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