Serotonin controls genes

The famous neurotransmitter regulates the packaging of DNA and the activity of genes in it

Kirill Stasevich, Science and Life (nkj.ru ) based on the materials of Nature: Modification of histone proteins by serotonin in the nucleus.

Serotonin is one of the many mediators used by nerve cells to transmit an electrical impulse to each other. When the pulse approaches the interneuronal junction – the synapse – the transmitting neuron releases a portion of the neurotransmitter, and the receiving one catches the neurotransmitter molecules with its receptors. The interaction of the neurotransmitter with the receptors opens ion channels in the membrane of the receiving neuron, the ions regroup on both sides of the membrane and an impulse arises that runs through the cell further to the next synapse.

But in fact, serotonin can affect the neuron much deeper than just forcing the transmission of an impulse. Serotonin receptors are known to be associated with changes in DNA packaging. We know that DNA in the cell nucleus is always accompanied by histone proteins, which either keep it in a tightly packed form, or, conversely, in an open unpacked form. Tightly packed DNA is inaccessible to other proteins that work with genetic information, on the contrary, information is actively read from unpacked DNA. 

The packaging and unpacking of DNA depends on the chemical labels on histones: special enzymes hang certain chemical groups on histones, and as a result, the activity of genes changes. For example, one gene is located in a section of DNA that histones have packed tightly because of their labels, and therefore such a gene is inactive; another gene may sit in a section of DNA that histones have unpacked, having previously received other labels on themselves - and such a gene will be active. (Histone modifications are one of the ways of epigenetic regulation of gene activity, which occurs not at the level of the genetic "text", but on top of it.)

Serotonin, as it was said, can control labels on histone packaging proteins through its receptors – the receptor, by binding serotonin, modifies some internal protein in the cytoplasm of the cell, it modifies someone else, and so the signal goes along the chain to the nucleus, to the enzyme that works with histones.

However, as stated in a recent article in Nature (Farrelly et al., Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3), serotonin itself can change DNA packaging. Cells have transglutaminase enzymes that attach serotonin to glutamic acid residues in a protein molecule. This modification is called serotonylation, and it has so far been seen in some cytoplasmic proteins that play a role in the division of smooth muscle cells, the release of insulin by pancreatic cells and other important processes.

On the other hand, one of these enzymes, transglutaminase 2, was found in the nucleus, and serotonin was found in the nucleus. And now researchers from Mount Sinai Medical Center, the Salk Institute and other research centers in the USA, Germany and China have found that one of the packaging histones actually receives a serotonin label, and it receives it only if that area of the molecule is already labeled with three methyl groups. Three methyl groups help unpack DNA, and so does serotonin – experiments with mouse and human neurons have shown that those genes that are next to serotonylated histone are more active than without a serotonin label. That is, the serotonin label and the trimethyl label are interconnected and work to activate genes.

Here, questions immediately arise about how serotonin interacts with other labels on histones, and how nuclear serotonin reserves are replenished (what role does the serotonin that floats outside the neuron play here), and what can be said about other neurotransmitters – can they also act as direct regulators of genetic activity. 

But the most intriguing questions are, of course, related to possible neuropsychiatric effects. Usually serotonin is recalled in connection with depression, although it can act on behavior in very different ways. Could it be that the effects of serotonin as a neurotransmitter are also reinforced at the gene level? Could it be that serotonin makes neural circuits more (or less) sensitive to some signals for a long time due to its work with histones? However, no matter how many hypotheses we come up with, they will still require experimental verification.

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