Epigenome: a parallel reality inside the cell

To understand what an epigenome and epigenetics are, you first need to clarify what genome and genetics are. A genome is a collection of genes from an organism. Genetics is a science that studies the mechanisms of realization of genetic information and transmission of genes to offspring. Accordingly, an epigenome is a set of specific labels that determine the activity of genes, but do not affect the primary structure of DNA. The epigenome (the prefix “epi-” means “above” in Greek) is a kind of regulatory layer located “above” the cell genome. Relatively speaking, the epigenome gives commands to which genes should work (be expressed), and which ones should rest (or “be silent”, that is, be in a state of silencing). Epigenetics is a scientific field that studies epigenetic modifications of the genome, ways of realizing gene states, their transmission in cellular generations, and mechanisms for regulating hereditary information (without changing the nucleotide sequence) in response to external factors [1].

Since the first discoveries in the field of genetics and until recently, the idea that the structure of DNA is the only carrier of hereditary information has been firmly entrenched in science. Thanks to large—scale decoding of genomes, including human ones [2], the nature of the gene and mutations — violations of the genetic record – were revealed, the principles of DNA organization were understood, and the nucleotide sequences responsible for hereditary pathologies were studied. It was found that human genetic information is stored in 23 pairs of chromosomes containing 20-25 thousand genes (it turned out that it is also not very easy to accurately determine their number [3]), or three billion pairs of nucleotides carrying mainly four types of nitrogenous bases: adenine, thymine, guanine, cytosine (abbreviated as A, T, G, C). However, the role of external factors in the mechanisms of realization of genetic information has been minimized. Simply put, scientists believed: what is written into the genome cannot be cut down with an axe [4].

Indeed, DNA is the foundation of most life forms. Its structure contains everything about a living organism, starting with its species characteristics, morphological parameters, predispositions to diseases, ending with the type of higher nervous activity, behavioral characteristics and inclinations. But it would be wrong to perceive the genome as a kind of fate that determines the life of an individual in advance. Not all genetic “predictions” are destined to come true: some of them will be rewritten more than once during ontogenesis (individual development of the organism).

During a long search, biologists made a number of interesting observations. For example, genetically identical laboratory mice consumed food of different composition during pregnancy. Some mice received food enriched with biologically active additives, in particular folic acid— a source of methyl groups, while others ate depleted food. The offspring of the mice eventually acquired morphological and physiological differences. Mice born to mothers who consumed enriched food were healthy and had a brown color, while mice born to mothers who ate poorly were sickly and had a yellow color. Thus, it was found that poor-quality nutrition, figuratively speaking, “turned off” some genes in the offspring responsible for both coat color and immune resistance. The traits acquired by individuals were passed on to offspring. At the same time, the set of genes (genotype) itself remained unchanged, that is, the DNA sequences were not affected [5].

Over time, scientists have come to the conclusion that the activity of many genes is unstable: they turn on (expressed) and off (repressed) depending on the effects of external factors. This change in gene activity, which does not affect the primary structure of DNA, but affects the manifestation of certain properties and traits, has become the subject of the study of epigenetics.

Epigenetics is a relatively young field of science. The term was first used in 1942 by the English scientist Conrad Waddington. By studying a number of patterns, the scientific community has come to the conclusion that the functions of a living organism are not determined solely by information encoded in genes, but largely serve as a response to signals from the environment. The epigenetically determined switching on and off of certain genes has become one of the most important discoveries of our time, for which American researchers were awarded the Nobel Prize in 2006 [10].

Classical Mendelian genetics is based on the fact that changes in phenotypic traits are based on DNA mutations, that is, mechanical — accidental or induced — changes in the structure of hereditary information. Epigenetics is based on variants of the norm, represented by modifications. Each of the epigenome disorders is no less important than genetic disorders, and acts as the epigenetic equivalent of a genetic mutation. However, despite its importance, epigenetics still remains secondary to genetics, its younger sister, an offshoot, and not an independent science. Since the main carrier of hereditary information is the genome, epigenetic mechanisms can only control the work of certain genes based on the available material. The epigenome serves as a mechanism for controlling the implementation of genetic information, which is carried out through modifications of individual nucleotides. Simply put, not all the genes we have work. Some genes are active in one cell and inactive in another, and vice versa. There are certain regulatory elements that control the activity of genes. According to modern concepts, such elements include: DNA methylation, histone modifications, acetylation, phosphorylation, glycosylation, various microRNAs and other structures/processes that “conduct” our genome [10], [11].

Consider the most famous and most important modification, DNA methylation. This is the only chemical modification of DNA involved in many genetic processes in eukaryotes. Methylation is the addition of a CH3 group to cytosine by DNA methyltransferase enzymes (Fig. 1), which leads to the inactivation of the entire gene containing this modified nucleotide.