The findings point to a novel mechanism for how neurotransmitters affect sleep/wake cycles and offer potential insights for treating circadian-related disorders.
Summary: A collaborative study by Mount Sinai and Memorial Sloan Kettering Cancer Center has revealed a new role for monoamine neurotransmitters like serotonin, dopamine, and histamine in regulating circadian rhythms and behavior. The research identifies how these neurotransmitters chemically bond to histone proteins, influencing gene expression patterns and neural activity. This mechanism, facilitated by the enzyme transglutaminase 2 (TG2), offers insights into circadian-related disruptions and potential therapeutic strategies for conditions like insomnia, depression, and neurodegenerative diseases.
Key Takeaways:
- Histone Modifications and Circadian Rhythms: The study uncovered that monoamine neurotransmitters, including histamine, can chemically bond to histone proteins, regulating circadian gene expression and influencing sleep/wake cycles and behavior.
- Novel Enzymatic Role of TG2: Transglutaminase 2 was found to not only add neurotransmitters to histones but also replace or remove them, dynamically altering gene expression patterns in response to environmental stimuli.
- Therapeutic Potential: The findings highlight a neurotransmission-independent mechanism for circadian regulation and suggest new pathways for developing treatments for disorders like insomnia, depression, and Parkinson’s disease.
A collaborative effort between Mount Sinai and Memorial Sloan Kettering Cancer Center has shed light on how monoamine neurotransmitters such as serotonin, dopamine, and now histamine help regulate brain physiology and behavior through chemical bonding of these monoamines to histone proteins, the core DNA-packaging proteins of our cells.
By uncovering how these histone modifications influence the brain, the team has identified a novel mechanism for controlling circadian gene expression and behavioral rhythms.
The team’s findings, published in Nature, could eventually guide the development of targeted therapies for conditions involving circadian rhythm disruptions, such as insomnia, depression, bipolar disorder, and neurodegenerative disease.
Novel Role of Monoamines in Circadian Gene Regulation
“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,” says lead author Ian Maze, PhD, Howard Hughes Medical Institute Investigator, professor of neuroscience and pharmacological sciences at the Icahn School of Medicine at Mount Sinai, and director of the Center for Neural Epigenome Engineering at Mount Sinai, in a release.
“This groundbreaking mechanism reveals, 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 leads The Yael David Lab at Memorial Sloan Kettering Cancer Center and co-lead author of the study, in a release. “We’re committed to gaining a more comprehensive understanding of these mechanisms so that this work can eventually contribute to the development of therapeutic strategies for treating circadian-related and other brain disorders.”
TG2 and Histone Modifications
Past work by the Maze Laboratory found that serotonin and dopamine, in addition to their role as neurotransmitters—chemical messengers that carry signals between nerve cells, controlling a multitude of vital bodily functions—can also attach to histone proteins, specifically H3.
These proteins directly modulate gene expression programs in the brain that contribute to complex biological processes and behavior (including neurodevelopment, drug relapse vulnerability, and stress susceptibility) and contribute to disease, when perturbed. The lab further learned 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 with an ability to not only add monoamines to histone H3 but also erase and exchange one monoamine neurotransmitter for another on H3, with different monoamines controlling gene expression patterns through independent mechanisms.
“The idea originated from a simple observation of the chemical intermediates formed by TG2 with its co-factor, revealing a new dynamic,” says study first author, Qingfei Zheng, PhD, a previous postdoctoral fellow in the Yael David Lab, who is now a faculty member at Purdue University, in a release.
Maze says, “These findings, among the first of their kind, imply that multiple brain regions, which can harbor heterogenous pools of monoamines, may rapidly exchange monoamines on histones in response to external stimuli to directly regulate gene expression programs.”
Implications for Circadian Rhythms and Beyond
“This unique mechanism suggests that additional histone monoamine modifications could be dynamically regulated, potentially playing roles in controlling complex events in the brain,” adds David in a release.
Based on this novel mechanism of action, the team speculated that intracellular fluctuations in monoamine concentrations can lead to their selective utilization by TG2, which could then trigger new histone modifications. Indeed, investigators identified histaminylation (referring to TG2’s reaction with the metabolic donor histamine) as a new modification of histones and showed that it, along with the allied process known as H3 serotonylation, plays a critical role in regulating circadian rhythms in the mouse brain, along with circadian behavior.
“Histaminylation also suggests a novel neurotransmission-independent mechanism for how our brains control sleep/wake cycles, which are disrupted in many disorders,” Maze says in a release.
Given the pivotal role histamine plays in other biological processes and disease states, including immune system regulation and cancer, researchers are now interested in further exploring how TG2-dependent monoaminylation of histones is controlled.
“By elucidating TG2 regulatory mechanisms, we may be able to gain valuable insights on diseases of monoaminergic dysregulation, including depression, schizophrenia, and Parkinson’s disease. Our work truly represents a foundational study that will hopefully lead to more advanced research in humans, with important therapeutic implications,” concludes Maze in a release.
Photo caption: Influence of histone monoaminylation dynamics on circadian gene expression
Photo credit: Benjamin Weekley, PhD, Icahn School of Medicine at Mount Sinai
