Study reveals how neurotransmitters influence brain gene expression

A study by researchers at Mount Sinai Health System and Memorial Sloan Kettering Cancer Center has discovered a mechanism that regulates gene expression in the brain. The team revealed how neurotransmitters like serotonin, dopamine, and histamine impact brain function and behaviour by bonding to histone proteins, which package DNA within cells. This discovery could lead to new therapies for circadian rhythm disruptions, including insomnia, depression, bipolar disorder, and neurodegenerative diseases. The findings, published in Nature on January 8, highlight how these monoamines, traditionally known for their roles as neurotransmitters, can directly modify histones to regulate gene expression patterns within the brain. 

“Our findings emphasise 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,” said Dr Ian Maze, the study’s lead author, Howard Hughes Medical Institute Investigator, and Professor of Neuroscience and Pharmacological Sciences at the Icahn School of Medicine at Mount Sinai.

Circadian events and DNA modification

The study builds on earlier work from Maze’s laboratory, which showed that serotonin and dopamine, in addition to their roles in neurotransmission, could also bind to histone proteins, specifically histone H3. These interactions directly modulate gene expression programs that contribute to various biological processes, including neurodevelopment, stress response, and behaviour. 

Dr Yael David, a chemical biologist at Memorial Sloan Kettering Cancer Center, emphasised the significance of these findings. “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,” she said. 

In their latest research, the team used an interdisciplinary approach to investigate the role of the enzyme transglutaminase 2 (TG2) in modifying histones. They found that TG2 regulates intracellular monoamine neurotransmitters, enabling the enzyme to not only add but also exchange and erase one monoamine neurotransmitter for another on histones. This process controls gene expression through independent mechanisms for different neurotransmitters.

The researchers suggest that these findings indicate that various brain regions, which host diverse pools of monoamines, may rapidly exchange monoamines on histones in response to external stimuli. This could directly regulate gene expression programs critical for brain function.  As part of their investigation, the team discovered a new modification of histones, termed histaminylation, in addition to the previously known H3 serotonylation. Both modifications were shown to play a critical role in regulating circadian rhythms and behaviours in the mouse brain. 

TG2’s role in neurodegenerative diseases

The team is particularly interested in exploring how TG2-dependent modifications may also be relevant to diseases associated with dysregulated monoamine neurotransmission, including depression, schizophrenia, and Parkinson’s disease. “By elucidating TG2 regulatory mechanisms, we may be able to gain valuable insights on diseases of monoaminergic dysregulation,” Maze concluded. “Our work truly represents a foundational study that will hopefully lead to more advanced research in humans, with important therapeutic implications.”

These findings have far-reaching potential, particularly in the development of novel therapies aimed at treating circadian-related disorders and a host of other conditions that involve disruptions to brain function. 

This study was published in Nature.