Set of chemical reactions and processes that modify the activity of DNA without altering its sequence. The genome is the alphabet and the epigenome, its accentuation or its grammar. Putting an accent or another can change the meaning of a word even if the word is the same. Some of these processes are DNA methylation and histone acetylation.
The term epigenetics was coined by the geneticist Conrad Waddington to define the study of the interactions between the genotype and the phenotype, that is, between the information encoded in the genes and that which is effectively expressed. Epigenetics studies the processes of gene expression that do not require the modification of the DNA sequence, in other words, without altering the reading of the nitrogenous bases adenine, cytosine, guanine and thymine.
The sequential order of these molecules in the coding regions of the genome determines the chemical nature of the proteins that are encoded by the genes and, consequently, their function. These processes can act throughout the life of the organism. From a neuronal point of view, recent proposals have defined epigenetics as «the structural adaptation of chromosomal regions to register, mark or perpetuate modified states of activity»
In short, epigenetics represents the different trajectories that a genotype can take throughout the development of the organism. Currently, two main mechanisms of epigenetic regulation have been identified, but up to now, more than twenty epigenetic mechanisms have been identified, which play a very important role in the regulation of transcription and, therefore, in gene expression.
These mechanisms include DNA methylation, post-translational modifications of histones, acetylation, ADP-ribosylation, ubiquitination, citrulation and phosphorylation, gene silencing mediated by non-coding RNAs, chromatin remodeling complexes based on adenosine triphosphate (ATP ) and the Polycomb and Trithorax protein complexes, among others.
MicroRNAs (miRNAs) are non-coding single-stranded RNA molecules, composed of 20-24 nucleotides that regulate gene expression negatively through different mechanisms at both the translational and post-translational levels.
The miRNAs are important regulators of the expression of mRNAs and have multiple targets, playing a fundamental role in the regulation of many biological processes. Abnormal expression of miRNAs has been described in cancer, metabolic disorders, diabetes and other diseases. Currently there are more than 460 known human miRNAs, and it is predicted that the total number would be much higher.
Our cells have gene expression patterns that can be altered and lead to cancer. Epigenetics is the study of changes in gene expression without causing changes in the DNA sequence.
Epigenetic and genetic alterations are considered as two independent mechanisms that participate in the appearance and progression of cancer. The epigenetics of cancer is providing new perspectives about it. There are two clear examples of epigenetic modifications in cancer cells.
Mechanism of action:
– It is believed that DNA methylation is responsible for the silencing of genes associated with paternal imprinting, heterochromatic gene repression and inactivation of the X chromosome. Cancer cells contain modified DNA methylation patterns, that is, they are much less methylated than normal cells. In addition, gene promoters in cancer cells are hypermethylated.
Therefore, it is believed that these modifications decrease the repression of transcription on most genes that would be silenced in normal cells. These methylation profiles are used today for the diagnosis of tumors. On the other hand, there are modifications in histones, which are also affected in cancer cells.
During the last decade it has been emphasized in the field of epigenetics to look for applications in the diagnosis and therapy of this disease together with microRNAs that play a very important role in the silencing of certain genes against certain conditions.
-Methylation of DNA: this phenomenon occurs when a methyl group is added to the base pair cytosine-guanine in the promoter region of the gene. In most cases, the consequence of DNA methylation is reduced expression of the gene or gene silencing, while a lower methylation is usually associated with greater activation in the transcription of the gene. In mammals the methylation of the DNA occurs by a covalent modification of the fifth carbon (C5) of the cytosine to which a methyl group (CH3) is added, finally obtaining 5-methylcytosine.
For example, in the case of cancer, certain anti-tumor genes, whose mission consists in stop the uncontrolled cell division, stop working because they are added several methyl groups (hypermethylation) in their regulatory regions.
These histone modifications are regulated by very specific enzymes. Depending on their activity, these enzymes are called writers (for example, if the enzyme adds a methyl group), erasers (for example if the enzyme removes a methyl group, such as the enzyme LSD1, present in several types of cancer) or readers ( if the enzyme can read or detect, the presence or absence of the methyl group).
-Acetylation of histones. Histones are globular proteins around which DNA coils recurrently. The DNA + histone complex is called a nucleosome and the nucleosome grouping is called chromatin, which in turn makes up the chromosomes.
A series of chemical phenomena (called acetylation, methylation, ubiquitination or phosphoacetylation) and carried out by histone-modifying proteins and the enzymes acetyltransferases, deacetylases or methyltransferases that change the positioning of histones are capable of altering the structure of chromatin, making it accessible or inaccessible to the transcription factors and consequently, modifying the expression of the gene.
Ubiquitin or ubiquitine is a small regulatory protein that has been found in most tissues of eukaryotic organisms. One of its many functions is to direct the recycling of proteins.
Ubiquitin can be associated with proteins and marked for destruction. Ubiquitin labeling directs proteins to the proteasome, which is a large protein complex found in the cell that degrades and recycles unnecessary proteins. This discovery won the Nobel Prize in chemistry in 2004
For example and in general, acetylation of histones opens chromatin to transcription factors and promotes the activation of gene function, and deacetylation determines the compaction of chromatin and the silencing of gene activity.
Epigenetics is a regulatory system that controls the expression of genes without affecting the composition of the genes themselves. The regulation of genetic transcription has emerged as a key biological determinant of protein production and cell differentiation, and plays an important pathogenic role in a number of human diseases.
This regulation is mediated by selective and reversible modifications of DNA and proteins, especially histones, which control the transition between transcriptionally active and inactive states of chromatin, are carried out by enzymes, many of which have specific genetic alterations that cause diseases human
The reversible inhibition of the activity of chromatin-modifying enzymes, associated with diseases, is an opportunity to create medicines based on small molecules as personalized therapy in diseases such as cancer, inflammatory diseases, metabolic diseases and neurodegenerative diseases.
Epigenetic research of behavior is accumulating an increasing number of evidences that point out the relevance of gene-environment interaction in the conformation of behavioral traits. In animal research contexts, it has been observed that the type of maternal care during the postnatal period modifies the epigenome of the glucocorticoid receptor in the hippocampus and that these changes are associated with different levels of response to stress.
The hypothesis of the histone code:
In the year 2001, Jenuwein and Allis proposed in their article: Translating the histone code (Science 10; 293 (5532): 1074-80) that the genome is partly regulated by chemical modifications in the histone proteins, mainly at their ends. structured. Histones associate with DNA to form chromatin fibers, which in turn form the chromosome.
The critical concept of the histone code hypothesis is that histone modifications serve to recruit other proteins by specific recognition of modified histone via specialized protein domains for these purposes, rather than simply stabilize or destabilize the interaction between histone and the underlying DNA. These proteins alter the structure of chromatin by silencing or activating whole regions of the chromosome and the genes located in it.
Until now it had been proven how the increase or lack of testosterone at a specific time of pregnancy could modify the sexual orientation of some rats, but it was evident that there were still points to clarify. Well, researchers at the University of California have qualified the theory including epigenetics.
Epigenetics studies those sets of factors that cause genes to end up expressing themselves in the subject or not. In this case researchers have found a group of these factors that regulates the response to testosterone and that is heritable, which would explain the existence of identical twins with different sexual orientation.
In patients with Post Finasteride Syndrome (SPF): possible epigenetic changes in the enzyme 5-alpha reductase, explain the complex symptoms, such as lack of libido, erectile dysfunction, etc., etc., that these people present (is in the phase of study).
On the other hand, the polycystic ovary syndrome (PCOS) is determined by genetic and epigenetic alterations, that is to say, various genetic markers that have a low predictive power (polymorphisms) and the epigenetic modifications generated by the environment (intrauterine or external), with the advantage that they can be reversible.
In addition, the family environment and the educational style impact not only on the behavior and emotions of the child, but also affect the development of hormonal response systems, neurophysiological and genotype expression.
In summary, epigenetic mechanisms allow us to understand the interaction between genes and environment, that is, the process by which the environment interacts with the genome and produces individual differences in the expression of specific traits and diseases, and not all we are is determined by our DNA sequence.
That process works thanks to chemical indicators called epigenetic biomarkers. The indicators stick to the DNA and tell the cells to use or ignore a particular gene.
The most common indicator is a type of molecule called the methyl group, methyl groups usually become hydroxymethyl groups. Then, they are diluted and disappear in the germ cells, which then become sperm and eggs.
When disappearing during the creation of the germ cells, the way in which the cells of the offspring reinterpret those genes is reprogrammed. However, a few methyl groups are saved from that reprogramming, appear in the germ cells and are inherited from parents to children.
All this supposes that rather than genetically predetermined, our life is epigenetically determined, although also inherited, diet and other environmental influences can influence our lives by modifying the genetic information and that of our offspring.
These new findings provide a better understanding of the mechanisms involved in the onset and development of the disease or aging and, given its reversible nature, open new paths for therapeutic intervention.
The great challenge for the immediate future, after concluding the map of the human genome in 2003, is to develop the epigenome map, when it has been achieved, we will have new biomarkers and therefore be able to diagnose and treat various diseases.
The epigenome is influenced by environmental factors, exercise, diet or exposure to toxic chemicals, among others, so it is a very valuable information for our health.