Neurotransmitters regulate the body clock by rearranging DNA

Serotonin and dopamine are often characterized as the “feel good” chemicals that flood our brains during moments of pleasure. While it's true that these chemicals help us feel better, they are more accurately described as neurotransmitters, chemicals that carry messages from one neuron to another. Research published over the past five years has revealed additional functions for these neurotransmitters. Serotonin and dopamine can regulate gene expression in the brain in the following ways: It binds to histones, a type of protein that acts like a spool around which DNA is wrapped. New research published in nature demonstrated that histamine, another neurotransmitter, 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).

This work was led by Ian MaysA neuroepigenetics researcher at the Icahn School of Medicine at Mount Sinai and the Howard Hughes Medical Institute, he published the first paper showing that serotonin can bind to histones. In a new study, Maze and colleagues found that histamine may bind to the same sites as serotonin and dopamine. That site is a glutamine unit near the end of the tail of the H3 histone called H3Q5. Right next to that glutamine is lysine, H3K4, which is a common site of methylation. Methylation at H3K4 promotes transcription of genes near histones, and marking H3Q5 with serotonin helps maintain its methylation and gene expression. However, marking H3Q5 with histamine has the opposite effect, as it promotes the removal of H3K4 methylation and reduces gene expression.

Although serotonylation and histamination at H3Q5 cause opposite effects, the modifications themselves occur through the same enzyme, transglutaminase 2 (TG2). Using the same enzyme to add and remove multiple types of neurotransmitters from histones creates interesting epigenetic dynamics, Mays said. “One of the important things to keep in mind is when: [TG2] Even if you remove the mark, the mutation actually remains at that site because it converts glutamate to glutamic acid,” Mays says. Thus, rather than simply removing neurotransmitters from histones, TG2 exchanges one neurotransmitter for another. Such mutations are involved in some cancers, he says, because “we don't want the histones to mutate.”

Song Hong JoonNeurobiologists at the University of Pennsylvania, who were not involved in the study, say that given the addition and removal of other histone modifications, including methylation, “TG2 may have multiple functions as an eraser, writer, and exchanger. That's interesting and surprising.” carried out by various enzymes.

Dr. Mays said the exchange of neurotransmitters on histones, and the fact that serotonylation and histamineation have opposing effects on gene expression, suggests that this process is linked to circadian rhythms, the natural processes in the body between wakefulness and rest. This suggests that it may be an element of a similar cycle. It's “kind of a yin-yang situation when you switch between serotonin and histamine,” he says. Working in mice, Mays and colleagues found that histone serotonylation promotes gene expression while the animals sleep. While they were awake, histamination suppressed gene expression in at least some genes. In particular, humans have different sleep cycles than mice, so the circadian dynamics of histone serotonylation and histaminization need to be confirmed in humans, but Professor Mays is hopeful that this research will be successfully translated.

Professor Mays said the study could help to better understand diseases associated with circadian rhythm disruption, but that there was “a long way to go” before its clinical relevance could be explored. ” he added.