A recent joint study has provided important insights into how monoamine neurotransmitters, including serotonin, dopamine, and now histamine, play a role in managing brain function and behavior. This occurs through the bonding of these compounds to histone proteins, which are essential for packaging DNA within our cells.
A collaborative project between Mount Sinai and Memorial Sloan Kettering Cancer Center has elucidated how monoamine neurotransmitters—including serotonin, dopamine, and now histamine—regulate brain function and behavior by chemically bonding to histone proteins, which are crucial for packing DNA in our cells.
The research team has explored how modifications to histones affect brain function, discovering a new way to control circadian gene expression and behavioral rhythms. The results, published in Nature on January 8, could inform the creation of targeted treatments for disorders related to circadian rhythm disruptions, such as insomnia, depression, bipolar disorder, and neurodegenerative diseases.
Lead author Ian Maze, PhD, a Howard Hughes Medical Institute Investigator and Professor at the Icahn School of Medicine at Mount Sinai, states, “Our findings highlight that the brain’s internal clock is influenced by chemical monoamine neurotransmitters in a previously unrecognized way. These monoamines can modify histones directly, influencing brain circadian gene expression patterns, neural plasticity, and cycles of sleep and wakefulness.”
Yael David, PhD, a chemical biologist and co-lead author, adds, “This innovative mechanism shows for the first time how circadian events that initiate neurotransmitter signaling, or vice versa, can significantly affect neurons by directly modifying the structure of DNA. We aim to deepen our understanding of these processes to develop effective therapeutic strategies for disorders tied to circadian rhythms and other brain conditions.”
Previous research from Maze’s lab indicated that serotonin and dopamine are not only neurotransmitters—chemical messengers that convey signals between nerve cells—but also attach to histone proteins, particularly H3. This attachment influences gene expression in the brain, impacting various biological functions and behaviors, including neurodevelopment and stress response, and can contribute to disease when disrupted. Furthermore, the lab identified transglutaminase 2 (TG2) as the enzyme responsible for adding serotonin and dopamine to histones.
In their latest investigation, researchers from Mount Sinai and Memorial Sloan Kettering Cancer Center utilized a multidisciplinary approach to analyze TG2’s biochemical mechanism. They discovered that TG2 regulates intracellular monoamine neurotransmitters and not only adds but can also remove or swap one monoamine for another on histone H3, allowing different monoamines to direct gene expression in distinct ways.
Study first author Qingfei Zheng, PhD, who was previously a postdoctoral fellow in David’s lab and is now a faculty member at Purdue University, notes, “The concept stemmed from a straightforward observation of chemical intermediates produced by TG2 with its co-factor, revealing a new dynamic.”
“These pioneering findings suggest that various brain regions, which may contain diverse pools of monoamines, can swiftly exchange these chemicals on histones in reaction to external stimuli, thus directly regulating gene expression,” explains Dr. Maze.
Dr. David adds, “This distinct mechanism indicates that additional modifications of histones by monoamines could be dynamically controlled, potentially influencing complex brain processes.”
Based on this novel understanding, the researchers theorized that changes in intracellular monoamine levels might allow TG2 to selectively utilize them, leading to new histone modifications. They identified histaminylation—TG2’s interaction with the metabolic donor histamine—as a new modification of histones, which, together with H3 serotonylation, plays an essential role in regulating circadian rhythms and behaviors in mice.
“Histaminylation suggests an innovative mechanism, independent of neurotransmission, by which our brains manage sleep and wake cycles—activities often disrupted in many disorders,” Dr. Maze explains.
Given histamine’s significant role in various biological functions and diseases, including immune regulation and cancer, researchers are interested in further investigating how TG2-mediated monoaminylation of histones is controlled.
Dr. Maze concludes, “By clarifying TG2’s regulatory mechanisms, we may uncover critical insights into diseases associated with monoamine dysregulation, such as depression, schizophrenia, and Parkinson’s disease. Our research lays a foundation for more extensive studies in humans with considerable therapeutic potential.”
Co-authors of the study from the Icahn School of Medicine at Mount Sinai include: Benjamin Weekley, PhD; David Vinson, PhD; Ryan Bastle, PhD; Aarthi Ramakrishnan, MS; Ashley Cunningham, PhD Candidate; Sohini Dutta, PhD; Jennifer Chan, PhD; Min Chen, PhD; Sasha Fulton, PhD Candidate; Giuseppina Di Salvo, Associate Researcher; Lingchun Kong, PhD; Lauren Dierdorff, PhD Candidate; Li Shen, PhD; Shuai Zhao (PhD Candidate, Tsinghua University); Robert Thompson, PhD (Princeton University); Stephanie Stransky, PhD (Albert Einstein College of Medicine); Nan Zhang, PhD (Ohio State University); Jinghua Wu, PhD (Purdue University); Haifeng Wang, PhD (Tsinghua University); Baichao Zhang, PhD (Tsinghua University); Lauren Vostal (Memorial Sloan Kettering Cancer Center); Akhil Upad (Memorial Sloan Kettering Cancer Center); Henrik Molina, PhD (The Rockefeller University); Simone Sidoli, PhD (Albert Einstein College of Medicine); Tom Muir, PhD (Princeton University); Haitao Li, PhD (Tsinghua University);
