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Neuroscience

Neurotransmitters regulate the body’s clock by reorganizing DNA

Dopamine, serotonin, and histamine carry messages between neurons. They can also influence circadian gene expression

by Max Barnhart
January 16, 2025

 

A graphic image of orange colored DNA, wrapped around three groups of blue histone protein polymers.
Credit: Shutterstock
DNA coils around groups of proteins called histones. When neurotransmitters such as serotonin, dopamine, and histamine, bind to histones, they can regulate gene expression.

Serotonin and dopamine are often characterized as “feel good” chemicals that flood our brains during moments of pleasure. It’s true that those chemicals can help us feel good, but they’re more precisely described as neurotransmitters—chemicals that carry messages from one neuron to another. Research published in the last 5 years uncovered another function for these neurotransmitters: serotonin and dopamine can regulate gene expression in the brain by binding to histones, a class of proteins that act like spools for DNA to coil around. New research published in Nature has demonstrated that another neurotransmitter, histamine, can also bind to histones and does so in a way that helps regulate the body’s circadian clock (2025, DOI: 10.1038/s41586-024-08371-3).

The work was led by Ian Maze, a neuroepigeneticist at the Icahn School of Medicine at Mount Sinai and Howard Hughes Medical Institute who published the initial paper showing that serotonin could bind to histones. In the new study, Maze and colleagues found that histamine could bind to the same site as serotonin and dopamine; that site is a glutamine unit near the end of the tail on H3 histones called H3Q5. Right next to that glutamine is a lysine, H3K4, that is a common site for methylation. Methylation at H3K4 promotes transcription of genes near the histone, and marking H3Q5 with a serotonin helps maintain that methylation and gene expression. Marking H3Q5 with a histamine does the opposite, however, as it promotes removal of the methylation at H3K4 and reduces gene expression.

Although serotonylation and histaminylation at H3Q5 cause opposite effects, the modifications themselves are made via the same enzyme: transglutaminase 2 (TG2). According to Maze, using the same enzyme to add and remove multiple kinds of neurotransmitters from histones leads to some intriguing epigenetic dynamics. “One of the key things to keep in mind is when [TG2] removes the marks, it actually leaves a mutation at that site, because it converts the glutamate to glutamic acid,” Maze says. So instead of simply removing the neurotransmitter from a histone, TG2 exchanges one neurotransmitter for another, “because you don’t want to mutate histones,” as such mutations are implicated in some cancers, he says.

Hongjun Song, a neurobiologist at the University of Pennsylvania who was not involved in the research, says it’s “interesting and surprising that TG2 can have multiple functions as eraser, writer, and exchanger” given that the addition and removal of other histone modifications, including methylation, are carried out by different enzymes.

Maze says the exchange of neurotransmitters on histones, and the fact that serotonylation and histaminylation have opposing effects on gene expression, suggests that this process might be a component of circadian rhythm—the natural cycle of bodily processes between waking and rest. It’s “kind of a yin and yang type of situation when you switch between serotonin and histamine,” he says. Maze and colleagues, who worked with mice, found that serotonylation on the histone promoted gene expression while the animals slept; while they were awake, histaminylation repressed gene expression, at least for some genes. The circadian dynamics of histone serotonylation and histaminylation still needs to be confirmed in humans, especially as humans have a sleep cycle different from that of mice, but Maze expects the work to translate well.

And though Maze says this work could help us better understand diseases related to circadian rhythm disruption, he adds that “we have a long way to go to” before probing its clinical relevance.

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