A recent collaborative effort between Mount Sinai and Memorial Sloan Kettering Cancer Center has provided new insights into the role of monoamine neurotransmitters—specifically serotonin, dopamine, and now histamine—in regulating brain physiology and behavior. This groundbreaking research uncovers how these neurotransmitters influence brain function by chemically bonding to histone proteins, which are core DNA-packaging proteins within our cells. By understanding this novel mechanism, the research team has shed light on how these modifications can control circadian gene expression and influence behavioral rhythms. Their findings, published in Nature on January 8, 2025, open up new possibilities for targeted therapies aimed at conditions related to circadian rhythm disruptions, including insomnia, depression, bipolar disorder, and neurodegenerative diseases.
The study emphasizes that the brain’s internal clock is influenced by neurotransmitter signaling in a way that has not been fully appreciated before. Monoamine neurotransmitters, like serotonin and dopamine, have long been known to serve as chemical messengers that carry signals between nerve cells, governing vital bodily functions and behavior. However, the discovery that these neurotransmitters can attach to histone proteins, particularly the histone H3 variant, directly affecting gene expression in the brain, adds a new layer of complexity to our understanding of brain function. This research indicates that neurotransmitters are not just involved in signaling but also in altering DNA structure to regulate gene expression, neural plasticity, and sleep-wake cycles, all of which are critical for brain health.
Lead author Ian Maze, Ph.D., a Howard Hughes Medical Institute Investigator and Professor of Neuroscience and Pharmacological Sciences at the Icahn School of Medicine at Mount Sinai, explained, “Our findings emphasize that the brain’s internal clock is influenced by chemical monoamine neurotransmitters in a manner not previously appreciated, such that monoamines can directly modify histones, which in turn regulate brain circadian gene expression patterns, neural plasticity, and sleep or wakefulness activity.” This revelation adds a significant dimension to our understanding of how neurotransmitter signaling and circadian rhythms are intricately connected.
The findings from this research suggest that the brain’s internal circadian clock is not solely regulated by external light and dark cycles, but also by the chemical fluctuations of neurotransmitters within the brain. These fluctuations can modify histones in the brain, leading to changes in gene expression and influencing circadian rhythms and behavior. This discovery is a major step forward in understanding the molecular mechanisms that underlie the body’s internal clock and its role in regulating sleep patterns and behavior.
One of the most important aspects of this study is the identification of transglutaminase 2 (TG2) as the enzyme responsible for modifying histones with neurotransmitters like serotonin and dopamine. The Maze Laboratory previously found that serotonin and dopamine could attach to histone proteins, specifically histone H3, and influence gene expression in the brain. This discovery was groundbreaking in itself, but the latest research takes it further by demonstrating how TG2 plays a central role in modifying histones with neurotransmitters and controlling gene expression.
The researchers at Mount Sinai and Memorial Sloan Kettering Cancer Center used a highly interdisciplinary approach to study the biochemical mechanism of TG2. The team found that TG2 does more than just add neurotransmitters to histones. It can also erase and exchange one neurotransmitter for another on histone H3, with different neurotransmitters controlling gene expression through independent mechanisms. This discovery reveals a previously unknown level of complexity in how the brain regulates gene expression in response to fluctuations in neurotransmitter levels.
Qingfei Zheng, Ph.D., a previous postdoctoral fellow in the Yael David Lab and now a faculty member at Purdue University, was the first author of the study. Zheng explained, “The idea originated from a simple observation of the chemical intermediates formed by TG2 with its co-factor, revealing a new dynamic.” This new dynamic involves the rapid exchange of neurotransmitters on histones in response to external stimuli, such as changes in light, activity, or stress. This process likely plays a role in how different brain regions regulate gene expression to adapt to the environment.
The team speculates that fluctuations in monoamine neurotransmitter concentrations could trigger TG2 to modify histones, which in turn regulates gene expression. One of the most significant findings of the study is the identification of histaminylation as a new modification of histones. Histaminylation refers to TG2’s reaction with the neurotransmitter histamine, resulting in a new histone modification that regulates circadian rhythms and behavior in the mouse brain.
“Histaminylation also suggests a novel neurotransmission-independent mechanism for how our brains control sleep/wake cycles, which are disrupted in many disorders,” said Dr. Maze. This discovery could have far-reaching implications for understanding and treating disorders related to circadian rhythm disruptions, such as insomnia, depression, and bipolar disorder. Histamine’s role in regulating the immune system and its involvement in other diseases, including cancer, makes it an exciting area for further research. The researchers now hope to explore how TG2-dependent monoaminylation of histones is controlled and how this process might be harnessed for therapeutic purposes.
Given that histamine is involved in a variety of biological processes, including immune system regulation and neurotransmission, understanding how it interacts with histones could provide important insights into diseases that involve monoaminergic dysregulation. For example, conditions like depression, schizophrenia, and Parkinson’s disease, which are associated with imbalances in neurotransmitter systems, could be better understood through the lens of histone modification and TG2 regulation.
“Our work truly represents a foundational study that will hopefully lead to more advanced research in humans, with important therapeutic implications,” concluded Dr. Maze. The research opens up new possibilities for developing targeted treatments for disorders involving disrupted circadian rhythms and neurotransmitter imbalances. By targeting the enzymes and pathways involved in these processes, it may be possible to develop more effective therapies for a wide range of neurological and psychiatric conditions.
Reference: Ian Maze, Bidirectional histone monoaminylation dynamics regulate neural rhythmicity, Nature (2025). DOI: 10.1038/s41586-024-08371-3. www.nature.com/articles/s41586-024-08371-3