How Epigenetics can Fix Our Memory and much more
How new epigenetic tools could rewrite our understanding of memory and more
Matt Windsor, translated by Evgenia Ryabtseva
If the human genome is the book of life, then the epigenome is its editor. Epigenetic labels–chemical groups that activate and inactivate genes–allow an organism to produce more than 200 cell types using the same genetic code. Neuron development, for example, requires inactivation of a third of the genome.
Over the past decade, it has become clear that epigenetic mechanisms play a particularly active role in the human brain. For example, a study by the head of the Department of Neuroscience at the University of Alabama, Dr. David Sweat, demonstrated that memorizing and storing new information in memory is impossible without epigenetic labels. Other research groups have shown that epigenetic disorders are involved in the formation of many neurological diseases, including Alzheimer's disease, schizophrenia, depression and addiction.
According to Dr. Jeremy Day, an employee of the Department of Neuroscience at the University of Alabama, whose laboratory studies the role of epigenetic effects in learning, memorization and addiction, almost any neuronal phenomenon can be associated with central epigenetic programming of differentiation or cell functions, or information storage.
At the present stage, the rapidly improving complex of molecular tools provides scientists with the opportunity to perform unprecedented manipulations on the epigenome. Researchers are already using these tools to study in detail the epigenetic mechanisms associated with diseases and good health. They also conduct experiments that sound like science fiction, such as creating and deleting memories. The discoveries made with these tools may give rise to a "new era of epigenetic drugs" (see Jeremy Day's article in Dialogues in Clinical Neurosciences). It is possible that the drugs of the future, acting on epigenetic mechanisms, will restore age-related memory disorders and cure hereditary diseases, erase unpleasant memories during post-traumatic stress and enhance cognitive function.
Control-Alter-DeleteUsually, epigenome editing strategies involve the use of systems based on CRISPR (from the English clustered, regularly interspaced, short, palindromic repeats – short palindromic repeats, regularly arranged in groups) or TALE (from the English transcription activator-like effector – an effector similar to a transcription activator).
Both types of systems consist of bacterial cell components and can be programmed to deliver an epigenome-modifying enzyme to specific genes. To inactivate the target gene, researchers use enzymes such as DNA methyltransferase. On the other hand, the target gene can be activated by delivering an enzyme such as histone acetyltransferase to it (see below).
A slightly earlier TALE system requires the synthesis of a specialized protein acting as a pointing device. Therefore, CRISPR systems guided by easier-to-produce RNA sequences (see Fig. from The Scientist magazine), are quickly becoming a tool of choice. CRISPR's work is shown in more detail in the animated sidebar at the end of the article.
Until recently, researchers' capabilities were limited to using drugs such as histone deacetylase inhibitors that block epigenetic changes throughout the genome instead of affecting a specific target gene. Such globally active drugs allowed scientists to identify correlations between epigenetic changes and behavioral features and diseases, but not to prove the existence of a direct relationship between these factors. New precise epigenome editing tools allow you to add and remove even single epigenetic labels. This makes it possible to identify causal relationships and identify the most important epigenetic modifications in a certain condition. Scientists can also reproduce these modifications to confirm their findings. According to Day, we are moving from the simple possibility of observing changes to the possibility of controlled manipulation and reproduction of these changes.
He explains this by the example of identifying a modification associated with memory. In this case, the researcher can ask himself the following questions: "If we make such a modification, can we create a memory? Can we implant a memory into the brain by changing the epigenetic status?" Until now, no one could even imagine the possibility of such questions.
With the help of new generation gene sequencing techniques, researchers can create a complete catalog of epigenetic changes involved in the formation of, for example, new memories or the development of a certain disease. These new tools will allow us to figure out which of these changes are most important.
Creating memories with LightWith the help of another developing technology, called optoepigenetics, researchers can regulate the process of making epigenetic changes over time, which is extremely important in some situations.
For example, epigenetic changes associated with memorizing information are formed within a few minutes.
It took several weeks to make the necessary epigenetic change using earlier techniques. Today, researchers have at their disposal an original system developed by employees of the Massachusetts Institute of Technology using the light-activated protein cryptochrome-2 (Cry2). This protein helps the favorite model plant of geneticists, the Arabidopsis thaliana (Arabidopsis thaliana), bend towards sunlight. Under the influence of light, the Cry2 molecule changes its shape and binds to the auxiliary protein CIB1. Using TALE as a delivery system, the researchers place the Cry2 protein in close proximity to the target gene. After that, they introduce the CIB1 protein into the same region as part of a complex with an enzyme that introduces epigenetic changes. At the final stage, a fiber-optic cable connected to a light source is introduced into the same region. When the light is turned on, CIB1 binds to Cry2, delivering the enzyme to the target gene, over which epigenetic manipulation is performed. The whole procedure takes no more than 30 minutes. (For more details, see the animated sidebar at the end of the article.)
The use of optoepigenetic tools allows Day to make epigenetic modifications to target genes by turning on and off the light. Each of the light signals depicted above reflects the functioning of one neuron in the brain in real time. Researchers can compare the activity of individual neurons with certain behavioral events when training an animal to perform a new task.
Dr. Day demonstrates some of what is available in his laboratory
equipment for optoepigenetic manipulations.
Another advantage of optoepigenetics is the possibility of its application to certain regions of the brain and cell types, even to the processes of neurons connecting different regions of the brain.
Erasing memories, healing hereditary diseasesAccording to Day, the ultimate goal of working in this area of research is to develop new therapeutic approaches based on epigenetics.
In their latest work, the results of which are published online in the journal Annual Review of Pharmacology and Toxicology, Day and his colleagues identified four areas that could primarily take advantage of epigenetic therapeutic approaches. These include: treatment of post-traumatic syndrome, depression, schizophrenia, as well as cognitive impairment. In each of these cases, an increasing number of results of animal experiments and clinical studies indicate epigenetic disorders as a factor stimulating the progression of the disease.
For example, according to one of the modern hypotheses, epigenetic mechanisms contribute to the formation and preservation of terrible memories in post-traumatic syndrome. Making changes to epigenetic markers is theoretically capable of accelerating the extinction of conditional and situational fear and can be used in combination with cognitive behavioral therapy.
Epigenetic therapeutic approaches may have many other potential applications. They can be used to inactivate mutant genes that produce abnormal proteins, such as the huntingtin protein that causes the development of Huntington's chorea. The same approach can be applied in the opposite direction to activate "silent" genes in order to cure other diseases. Despite the fact that we receive copies of genes from both parents, one of these copies (an allele) can be inactivated by epigenetic labels during development. In diseases such as Angelman syndrome associated with severe mental and physical retardation, the active maternal allele of the gene is non-functional due to mutation, while the paternal allele is inactivated. The removal of epigenetic labels from the paternal allele should trigger the synthesis of the missing protein.
Day's lab staff are particularly interested in finding treatments for addiction. They believe that epigenetic changes resulting from drug exposure can persist in the human genome for a long time. This may explain the fact that a person who has been cured of addiction and has not used drugs for several years can suddenly return to addiction under the influence of a single stimulus, for example, a visual image. Being able to manipulate such changes would be a really powerful therapeutic approach to treating addiction.
Before highly effective epigenetic therapies are introduced into clinical practice, researchers still have many problems to solve. Identifying the exact therapeutic targets will require a large amount of basic research. Researchers will also have to improve the delivery methods of therapeutic systems, since injections and viral vectors currently used in animal experiments are not applicable in clinical practice. However, Day claims that, despite everything, today we are at a very promising stage. Given that epigenetic changes are characteristic of a huge number of conditions, in the near future we will begin to receive answers to questions that experts have been asking since time immemorial.
Editing the epigenomeNew high-precision techniques allow researchers to add and remove epigenetic labels on specific target genes.
Since these labels are associated with an ever-increasing number of diseases, including depression and Alzheimer's disease, new technologies inspire hope for deepening our knowledge and the emergence of new therapeutic approaches.
Epigenetic "writers"Usually methylation inactivates genes.
To methylate a particular gene, researchers attach the enzyme DNA methyltransferase to a carrier molecule, for example, an effector similar to a transcription activator (TALE), programmed to move to the target gene.
By adding epigenetic labels to histone proteins, researchers can increase gene expression. DNA is wound on histones and a thread on a spool. Using TALE to deliver a histone acetyltransferase enzyme, such as the binding protein Creb, the researchers add acetyl groups to protruding histone fragments. This "relaxes" the histones, opening the binding center of the target gene for enhanced transcription using RNA synthesis mechanisms.
Epigenetic "erasers"Removal of methyl groups from DNA, as a rule, increases gene expression.
This process consists of 2 stages. At the first stage, scientists use methylcytosine hydroxylase. After that, to demethylate the gene, they deliver thymine DNA glycosylase to the same region of the homosome.
Removing labels from histones reduces gene expression. Researchers deliver histone deacetylase such as histone deacetylase-2 (HDAC2) to the target gene, where it removes acetyl groups from protruding histone fragments. This closes access to the gene and blocks the mechanism of RNA synthesis.
Optoepigenetics: Using light to activate and inactivate genesCombining the photosensitive cryptochome-2 (Cry2) protein with target gene-specific carriers allows researchers to add or remove epigenetic tags within a few minutes.
Under the influence of blue light, the Cry2 protein molecule changes its shape and binds to the CIB1 protein. Researchers use this conformational change to trigger an epigenetic mechanism.
First, Cry2 is attached to a carrier molecule, such as TALE, programmed to move to a specific gene. At the same time, the CIB1 protein binds to an epigenetic effector protein, which, depending on the purpose of the experiment, attaches or removes epigenetic markers.
Cry2 is in a waiting state near the target gene, and CIB1 is in close proximity to it. When researchers are ready to make an epigenetic change, they turn on the blue light entering the modification zone via a pre-implanted optical fiber. Under the influence of light, the Cry2 molecule changes its shape and binds to CIB1. This ensures the delivery of the epigenetic effector to the target gene.
With the help of viral vectors, researchers can make changes in strictly limited regions of the brain, such as the prefrontal cortex, and even in certain types of cells, for example, dopaminergic neurons connecting the ventral region of the tire to the nucleus accumbens of the brain.
Brave New World of Epigenetic DrugsDespite the fact that they are still at the theoretical stage, drugs capable of adding or removing epigenetic labels with high accuracy may have several unique advantages over traditional medicines.
These qualitatively new benefits are described in an article by neuroscientist Jeremy Day from the University of Alabama at Birmingham and his colleagues, recently published in the journal Annual Review of Pharmacology and Toxicology.
A once-in-a-lifetime pill: Many modern drugs have a therapeutic effect only with prolonged use. However, due to natural self-maintenance mechanisms that ensure the stability of epigenetic markers, one dose of an epigenetic drug may be enough for a lifetime.
Therapy for several generations: Despite the fact that this issue is the subject of heated debate, there is quite convincing evidence that epigenetic markers can be inherited from parents to children. This means that changing the hereditary trait can help not only the patient himself, but also his descendants. This means the emergence of a completely new type of pharmacodynamics – the preservation of the effect of the drug even in the absence of an organism that has experienced its direct effect.
High precision therapy: epigenetic drugs will potentially have unprecedented specificity. Traditional medicines usually exert their effect by blocking receptors on the cell membrane. However, there may be many thousands of these receptors on the surface of a single cell. An epigenetic drug, on the contrary, will be able to inactivate the gene encoding the target receptor, which will completely eliminate its influence.
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