Mirror mirror on the wall, who’s the newest histone modification of all? We know that methylation, acetylation, phosphorylation, ubiquination, and even citrullination have been toiling away in the chromatin mines, but a new study from the brainy team who discovered serotonylation suggests that dopamine is also hard at work on histone tails, where it highlights the role of histone modifications and drug addiction.
Researchers from the lab of Ian Maze (Mount Sinai School of Medicine, New York) used a liquid chromatography-tandem mass spectrometry (LC-MS/MS), and found that the neurotransmitter binds to the fifth glutamine of histone H3 (H3Q5dop), just like it’s cousin serotonin (H3Q5ser).
Since dopamine is an important factor in drug addiction, the talented team looked for differences in H3Q5dop in post-mortem human brains and found that samples from the ventral tegmental area (VTA) of cocaine dependent people had less H3Q5dop. Next, they explored their newly discovered modification in rats, that were trained to work for cocaine and found that:
- The decrease in H3Q5dop in the VTA is transient and steadily returns to baseline by the 30th day of withdrawal from cocaine
- H3Q5dop levels are unchanged in the VTA of animals that have limited access to cocaine during their training, are passively injected with the drug, or are trained to work for food pellets instead
In order to understand the specifics of dopamine’s job in the nucleus, the savvy scientists decided to inject the VTA of rats with a lentivirus coding for a mutated H3 protein, before training them to self-administer cocaine. Using this assay, which prevents H3Q5dop from accumulating in the chromatin, they found that:
- The mutation reduces the overall impact of cocaine-induced gene expression changes, and reverses differential expression of genes that are involved in synaptic transmission and drug addiction, as measured by RNA-seq
- Mutant dopamine-producing neurons have fewer spontaneous action potentials than control cells, and release less dopamine in response to cocaine, as measured by fast-scanning cyclic voltammetry
- When mutant animals are trained to self-administer cocaine they are less likely to seek the drug after 30 days of withdrawal
Overall, it looks like dopamine has a very specific task when it comes to chromatin and cocaine; changing the level of H3Q5dop in the VTA has no impact on other drug-related behaviors such as cocaine-induced locomotor sensitization.
Take a look into the magic mirror and read the original article in Science, April 2020.