Groundbreaking research uncovers a new function of serotonin – the epigenetic regulation of gene expression

“Our findings represent a dramatic divergence from the current dogma, which works primarily on the premise that neurotransmitters like serotonin and dopamine act solely through the activation of their membrane receptors in the brain to regulate brain cell activity” 

– Dr Ian Maze, a senior author of the research.

I have previously written about the increasingly evident role of epigenetic modifications in the regulation of gene expression, and how these post-translational modifications can lead to a number of genetic changes involved in a host of psychiatric disorders; from major depression to PTSD to schizophrenia. If you haven’t already read that article, I suggest reading it first as it will help you to understand the basis of the exciting research which follows.

Structure of euchromatin
From Sun et al. (2013)

Serotonin, also known as 5-HT, has previously been shown to form covalent bonds with proteins in the cystoplasm of neurons via interactions with an enzyme called transglutaminase 2 (TGM2), leading to a change in the activity of those proteins. However, this is the first time that serotonin has been shown to bind to proteins in the nucleus – specifically the histone proteins which wrap around DNA-containing euchromatin (the active parts of the genome from which genes are transcribed) to form nucleosomes. Simply put, if the DNA encoding a gene is wound tightly within the nucleosome, it is less likely to be expressed; however if the gene is wound less tightly, it is more likely to be expressed. There are a multitude of modifications to these histone proteins which can alter the expression of the genes contained, such as methylation, acetylation or phosphorylation; but this is the first time that serotonin – a monoamine neurotransmitter – has been shown to directly interact with the genome through a histone modification dubbed “serotonylation”.

TGM2 enables serotonylation
of H3 by 5-HT (serotonin).
From Farrelly et al. (2019).

In the current study published earlier this week in Nature, Farrelly et al. show that serotonin is able to “serotonylate” particular histones via an interaction with the enzyme TGM2, ultimately leading to changes in the expression of the particular gene contained within the structure. TGM2 was shown to be both necessary and sufficient for serotonylation at H3, although the interaction was only found to occur at H3 histones. 

Mass spectrometry following in vitro TGM2 binding assays revealed Gln5 as the specific amino acid on H3 which binds serotonin via a TGM2-dependent interaction; this was confirmed by the observation that when Gln5 was mutated to a different amino acid, this “transamidation” interaction with serotonin could not occur. That is, the glutamine found at position 5 of the H3 histone of H3K4me3 nucleosomes is the particular site at which serotonin binds via TGM2. 

This histone serotonylation process was found to be significantly apparent – and perhaps even necessary – in pathways involved in neuronal development and differentiation. Interestingly, however, the modification was even shown to occur in non-serotonergic neurons, and yet more surprisingly, in non-neuronal cells. 

This suggests that serotonin – further to its role in neurotransmission – may play a role in activating the expression of genes throughout the brain and body by directly interacting with chromatin. While specific interactions with a common transcription factor complex called TFIID were demonstrated in neuronal growth pathways, precisely how histone serotonylation activates gene expression throughout the genome has yet to be elucidated. Nonetheless, this finding dramatically alters our understanding of the role of serotonin – and perhaps other neurotransmitters such as dopamine – in the body. 

Future research will investigate whether pathological changes in serotonin transmission – such as in mood disorders or as a result of the pharmacological action of drugs such as SSRIs – could interfere with this newly discovered role of serotonin. Dr. Maze’s laboratory is also investigating the role of other monoamine neurotransmitters, such as dopamine, in such histone modifications.

Source:

Farrelly, L.A., Thompson, R.E., Zhao, S., Lepack, A.E., Lyu, Y., Bhanu, N.V., Zhang, B., Loh, Y.-H.E., Ramakrishnan, A., Vadodaria, K.C., et al. (2019). Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3. Nature. Available at: https://doi.org/10.1038/s41586-019-1024-7.