Random news from the Archive Neurons change their own DNA
06.05.2015
The stability of DNA is the key to a long and happy life, so the cell tries to eliminate all mutations with the help of special molecular machines. Of course, here we can recall the phenomenon of crossing over, which occurs, for example, during the maturation of germ cells (and in dividing cells in general) - during crossing over, a large-scale exchange of DNA fragments occurs between homologous chromosomes.
However, this process is under careful control, and it is still tied to cell division. As for the other cases of genome instability, they arise either due to external causes (such as mutagenic radiation), or due to the not very precise work of molecular machines involved in DNA duplication and repair. A normal, healthy cell tries as closely as possible to monitor changes in chromosomes and, if possible, restore everything as it was.
All the more surprising are the results of Hongjun Song's research group at Johns Hopkins University. He and his collaborators found that normal, mature brain neurons are constantly making changes to their own DNA using epigenetic marks. As you know, in order to change the activity of a particular gene, the cell does not need to interfere with the nucleotide sequence, it is enough to supply the gene with special markers that will make it less attractive to proteins synthesizing RNA. These markers are methyl groups that are attached to the nitrogenous base of cytosine, one of the four "letters" of the genetic code. (In parentheses, just in case, we note that methyl marks and epigenetic regulation in general are far from the only way to control gene activity.)
DNA methylation is easy, but it happens that the label needs to be removed from cytosine. This is no longer so easy to do, and here a whole chain of reactions is launched, and along the way, the labeled "letter" is cut out and ordinary, unmethylated cytosine is inserted in its place. That is, a hole is formed in one of the DNA chains, which is a strong element of instability - after all, some other “letter” can mistakenly get here, and we will get a real mutation. Nevertheless, the processes of DNA methylation and demethylation are quite active in mammalian cells, even in such a “delicate” organ as the brain, which is generally protected to the maximum from an unpredictable external environment and from the rest of the body.
In their article in Nature Neuroscience, the authors write that in mouse brain neurons, demethylation activity was clearly associated with synaptic cell plasticity. Synaptic plasticity is understood as the ability of a neuron to regulate the strength of the interneuronal connection with its neighbors - thanks to it, the impulse in the chain can weaken or increase. At the molecular level, this can be seen by how the number of neurotransmitters that transmit a signal from one neuron to another changes, and how the number of neurotransmitter receptors at the "receiving side" changes - the wider the range of changes, the greater the plasticity of the neuron. So, when the Tet3 gene, which suppresses demethylation, was turned off in brain cells, synaptic plasticity increased; conversely, when Tet3 activity was stimulated, plasticity decreased.
Further experiments showed that the Tet3 gene affects the level of the synaptic GluR1 protein, which just serves as a receptor for neurotransmitters. If neurons began to respond to the most insignificant stimulus, Tet3 activity increased, and as a result, the GluR1 receptor level decreased - that is, cells stopped responding to the slightest changes in impulses, synapses returned to the standard mode of operation. But the opposite could also be true: if the activity of synapses was greatly reduced, in Tet3 it also decreased, so the level of GluR1 increased - which, in turn, was reflected in the work of synapses. The activity of the gene responsible for demethylation could be seen by the state of DNA, by how often a nucleotide was cut out in it.
Synaptic plasticity is associated with the ability to learn - it is believed that the more it is, the better for the brain. But it obviously must have some kind of regulators, one of which unexpectedly turned out to be the Tet3 gene, which reacts to changes in the activity of interneuronal contacts. Of course, the question arises of how exactly this "microsurgery" of DNA, that is, the constant cutting out of letters from a sequence of nucleotides, affects the ability of synapses to respond to different signals. It is possible that the gaps in the DNA chains fall precisely on those genes that directly affect the strength and sensitivity of synapses, but what exactly happens there can only be known from further research.
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