The Epigenetic Revolution
Article by Kara Rogers Epigenetics: A Turning Point in Our Understanding of Heredity
published in Scientific American Blogging Network.
Translated by Evgenia Ryabtseva
In the article Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans, published in 2011 in the journal Nature, a geneticist from Stanford University Anna Brunet and her colleagues describe a number of experiments in which they demonstrated that the lifespan of nematodes Caenorhabditis elegans, grown under the same conditions, can vary in a significant range. Individuals lived exceptionally long, and three generations of their descendants were also distinguished by longevity. It is obvious that the tendency to longevity was inherited, despite the identity of the genotypes of individuals with different life spans.
Recently, researchers have increasingly received similar data: inherited differences that cannot be explained by variations in the actual genetic material. In part, the increase in the number of such observations can be explained by the fact that currently experts already know that genes are not the only "authors" of the transmission of phenotypic traits to the next generations. They have assistants. At first glance, they look quite ordinary: methyl, acetyl and phosphoryl groups that attach to DNA–associated proteins, and sometimes even to DNA itself, and look at best like dependents.
A DNA molecule with methylated central cytosine on both chains
Their shape is far from the elegance of the curls of DNA encoding genes, they are transient and short-lived, in contrast to genes passed down from generation to generation over millions of years. However, they surreptitiously exert their influence by modifying DNA and regulating the work of genes, which makes changes in the chaos of nucleic and amino acids. It is for this reason that many researchers recognize the discovery of these objects, made at the end of the XX century, as a turning point for our understanding of the mechanisms of inheritance of traits, which resulted in perhaps one of the most important revolutions in modern biology – the emergence of epigenetics.
Epigenetics and chromatin stateIn the Brunet laboratory, epigenetic heredity is highly respected.
The article published by her collaborators in Nature was the first publication describing this phenomenon in relation to the inheritance of longevity from generation to generation. This breakthrough was the result of attempts to clarify the role of chromatin in inheritance mechanisms.
Chromatin is a compactly packed protein fiber and DNA. It can exist in two forms: heterochromatin (condensed) and euchromatin (loose). Chromatin passes into a condensed form during cell division, which facilitates the separation of chromosomes for their distribution between daughter cells. However, certain segments of fibers can retain this shape in non-dividing cells, while the genes encoded in such segments are fixed in an inactive state. Other fiber fragments, on the contrary, straighten and open, providing regulatory proteins with access to DNA and activating genes.
Certain epigenetic modifications, such as the attachment of methyl groups to histone proteins that act as bobbins on which DNA is wound during chromatin compaction, are necessary to maintain the DNA chain in the open state. However, the modifications are dynamic. For example, during the development of an organism, chemical groups attach and detach from histones or DNA in a certain order. Their "dance" contributes to the realization of important functions, such as the formation of gene expression profiles of various types of tissues and the suppression of the activity of parental genes – a phenomenon known as parental or genomic imprinting.
Modifications can also accumulate during the life of the organism. Since these acquisitions are able to change the DNA transmitted to the next generations through germ cells (giving rise to eggs and spermatozoa), and do not necessarily have a positive effect, they are eliminated during reproduction, and chromatin returns to its original state. However, this mechanism does not always work, and some modifications go unnoticed. In such cases, chromatin modifications in the parent DNA that have not passed the reprogramming process are passed on to the next generation.
Epigenetic inheritance of longevity in nematodesThere is increasing evidence that in many species epigenetic modifications are transgenerational (transmitted through many generations).
Examples include coat color in mammals, eye color in fruit flies, symmetry in flowers, and, finally, longevity in nematodes C.elegans. These data are extremely interesting and raise intriguing questions about the seemingly limitless possibilities of epigenetic heredity.
The difference in coat color in these two genetically identical mice
due to epigenetic modifications.
However, the work of deciphering epigenetic modifications and their effects is very difficult. In order to identify the role of methylation in the longevity of nematodes, Brunet and her colleagues began by estimating the lifespan of C.elegans that did not have one of the three genes – ash-2, wdr-5 or set-2. Previously, it was found that a decrease or absence of expression of these genes increases the life expectancy of representatives of this species. After that, they crossed nematodes with the corresponding genetic defects with nematodes having a normal genotype. Mating according to the classical rules of Mendel led to the appearance of both wild–type individuals (with a normal genotype) and individuals carrying genetic changes. The results of the life expectancy assessment for each of these populations were recorded and compared with the corresponding indicator obtained for the control population (wild-type nematodes that appeared as a result of mating of wild-type parental individuals). According to the data obtained, the nematodes of the control group were characterized by an average life expectancy, whereas wild-type nematodes, genetically identical to the individuals of the control group, but appeared as a result of crossing normal individuals with mutant individuals, lived 20-30% longer.
Thus, despite the fact that genetic defects were not inherited, they somehow exerted an influence that endowed genetically normal descendants with the same long life as their mutant ancestors. The Stanford team of scientists concluded that the nature of this change was methylation.
Proteins encoded by the ash-2, wdr-5 and set-2 genes are part of the histone methylation complex known as H3K4me3. This complex is present in the cells of many species, ranging from yeast to humans. However, the mechanisms that ensure the inheritance of longevity are unclear. Brunet explains: "We did not observe a general decrease in the content of H3K4me3 in the cells of genetically normal descendants of mutants who do not have this complex. In other words, there is no global H3K4me3 deficiency that would be inherited epigenetically." Thus, the model formulated by the researchers boils down to the following: in conditions of a lack or absence of proteins in certain places of the genome, H3K4me3 methylation is lost and chromatin state modifications associated with longevity or, possibly, other types of modifications (for example, non-coding RNAs) are transmitted to the following generation.
Transgenerational inheritance of acquired characteristics in humansEpigenetics has given new life to Lamarckism and the previously discarded idea that characteristics acquired by an organism during life can be inherited.
Many researchers have already begun to look at this idea in a different way. According to Brunet, "apparently, the Lamarckian concept is beginning to be recognized again (in relation to certain cases). This may change our understanding of inheritance, bringing a new component to Mendelian genetics, perhaps not very pronounced, but real."
It also adds a new level of significance to the conditions of our daily life for our descendants. A number of environmental factors, ranging from food to temperature and the presence of chemicals, can make changes in gene expression, and those that manage to penetrate the chromatin of the germ line and avoid reprogramming, theoretically can be passed on to our children, and possibly grandchildren.
However, while the results of a number of studies indicate that transgenerational epigenetic inheritance can occur in humans, there is very little real evidence of this. Among the most convincing cases to date is the synthetic analogue of estrogen diethylstilbestrol (DES), which in the middle of the XX century was used to prevent miscarriages in pregnant women. It turned out that diethylstilbestrol significantly increases the risk of congenital malformations of the fetus. Its use is also associated with an increased risk of vaginal and breast cancer in daughters and an increased risk of ovarian cancer in maternal granddaughters of women who have undergone appropriate therapy during pregnancy. The results of studies on mice indicate that exposure to diethylstilbestrol during the newborn period causes abnormalities in the methylation of genes involved in the formation of the uterus and the development of uterine cancer. In mice, these anomalies were detected even after two generations, which indicates the existence of a transgenerational effect.
Due to the unclear nature of the inherited epigenetic modifications, it seems that, despite the decades spent on research, scientists still cannot cross the threshold of understanding. However, the prospects look truly limitless, even considering that in order to turn into inherited epigenetic modifications must change the expression of genes in germ cells, which is rarely possible even for genetic mutations. However, observing the rapidly growing prevalence of conditions such as obesity, diabetes and autism, which in the vast majority of cases do not have a clear genetic etiology, Brunet emphasizes that "apparently, epigenetics influences all complex processes."
While researchers continue to search for unambiguous evidence of the existence of transgenerational epigenetic heredity in humans, the data obtained to date already indicate that our lifestyle, the food, drinks we consume and the air we inhale can have a direct impact on the genetic health of our descendants.
Portal "Eternal youth" http://vechnayamolodost.ru08.02.2012