A collaboration between Mount Sinai and Memorial Sloan Kettering Cancer Center has provided valuable insights into how monoamine neurotransmitters such as serotonin, dopamine, and now histamine contribute to the regulation of brain physiology and behavior through chemical binding of these monoamines to histone proteins, the nuclear proteins that package our cells’ DNA.

By revealing how these histone modifications affect the brain, the team has identified a novel mechanism for controlling circadian gene expression and behavioral rhythms. The team’s findings, published in Nature, may ultimately guide the development of targeted therapies for disorders involving circadian rhythm disruption, such as insomnia, depression, bipolar disorder, and neurodegenerative diseases.

How Circadian Events can Exert Dynamic Effects on Neurons

“Our findings highlight that the brain’s internal clock is influenced by the monoamine chemical neurotransmitters in a previously unrecognized manner, such that monoamines can directly modify histones, which in turn can affect the brain’s circadian gene expression patterns, neuronal plasticity, and wakefulness,” says lead author Ian Maze, PhD, a Howard Hughes Medical Institute investigator, professor of neuroscience and of pharmacological sciences at the Icahn School of Medicine at Mount Sinai, and director of the Center for the Entrainment of Cell Physiology (CECP). and wakefulness,” said lead author Ian Maze, PhD, a Howard Hughes Medical Institute investigator, professor of neuroscience and of pharmacological sciences at the Icahn School of Medicine at Mount Sinai, and director of the Center for Neural Epigenome Engineering at Mount Sinai. “This breakthrough mechanism demonstrates for the first time how circadian events that stimulate neurotransmitter signaling (or vice versa) in the brain can exert dynamic effects on neurons by directly altering DNA structure,” adds Yael David, PhD, a chemical biologist who heads the Yael David Lab at Memorial Sloan Kettering Cancer Center and is a co-author on the study.

Previous work by the Maze Laboratory revealed that serotonin and dopamine, in addition to their roles as neurotransmitters – chemical messengers that transmit signals between nerve cells and control a variety of vital bodily functions – can also bind to histone proteins, particularly H3. These proteins directly modulate gene expression programs in the brain that contribute to complex biological processes and behaviors (including neurodevelopment, susceptibility to drug relapse, and vulnerability to stress) and contribute to disease when disrupted. The laboratory also found that the enzyme responsible for modifying histones with serotonin and dopamine is transglutaminase 2 (TG2).

In their latest study, researchers from the Nash Family Department of Neuroscience and the Friedman Brain Institute at Mount Sinai and Memorial Sloan Kettering Cancer Center used a highly interdisciplinary approach to decipher the biochemical mechanism of TG2. The teams found that TG2 acts as a regulator of intracellular monoamine neurotransmitters, and not only can TG2 add monoamines to histone H3, but it can also erase one monoamine neurotransmitter on H3 and replace it with another, with different monoamines driving gene expression patterns by independent mechanisms.

What This Means for Disorders Such as Depression, Schizophrenia and Parkinson’s

Based on this novel mechanism of action, the team speculated that intracellular fluctuations in monoamine concentrations may lead to their selective utilization by TG2, which could then trigger new histone modifications. Indeed, the researchers identified histaminylation (which refers to the reaction of TG2 with the metabolic donor histamine) as a new modification of histones and showed that it plays a critical role, along with the related process known as H3 serotonylation, in regulating circadian rhythms in the brain of mice and circadian behavior.

Given histamine’s central role in other biological processes and disease states, including regulation of the immune system and cancer, researchers are now interested in further exploring how TG2-dependent monoaminylation of histones is controlled. “By elucidating the TG2 regulatory mechanisms, we may be able to gain valuable insights into diseases based on monoaminergic dysregulation, including depression, schizophrenia and Parkinson’s disease.” ‘Our work represents fundamental research that will hopefully lead to more advanced research in humans with important therapeutic implications,’ concluded Dr. Maze.