epigenetics today and tomorrow
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ISSN 20790597, Russian Journal of Genetics: Applied Research, 2014, Vol. 4, No. 3, pp. 168188. Pleiades Publishing, Ltd., 2014.Original Russian Text B.F. Vanyushin, 2013, published in Vavilovskii Zhurnal Genetiki i Selektsii, 2013, Vol. 17, No. 4/2, pp. 805832.
Genetics proposes, epigenetics disposes
Peter Medawar, Nobel laureate
It always seems that all scientists and expertsunderstand what epigenetics is, but everyone stillunderstands it differently. The term epigenetics wasproposed by K. Waddington as the study of the causal
mechanisms of realization of the genome (genes) inthe phenotype. He termed the phenotypic changesoccurring from cell to cell during the development of amulticellular organism phenotypic landscape. Infact, this is a very common and very indefinite concept(definition), which unites and represents the entiredevelopment of the organism, including all ontogenetic mechanisms. D.L. Nanney considers epigenetics
Epigenetics Today and TomorrowB. F. Vanyushin
Belozersky Institute of Physicochemical Biology, Moscow State University, Moscow, 119992 Russiaemail: email@example.com
Received June 3, 2013; in final form, November 1, 2013
AbstractEpigenetics is the science of the heritable properties of the organism that are not associated withchanges in the DNA nucleotide sequence but can be indirectly encoded in the genome. The most wellknownepigenetic mechanisms (signals) are enzymatic DNA methylation, the histone code (various enzymatic histone modifications including acetylation, methylation, phosphorylation, ubiquitination, etc.), and genesilencing mediated by small RNAs (miRNA, siRNA). All these processes are usually interconnected and evenpartially interchangeable. This is apparently required for the reliable implementation of epigenetic signaling.Anyway, these processes are closely associated with chromatin structural and functional organization. DNAmethylation in plants and animals, performed by sitespecific enzymes, cytosine DNAmethyltransferases,produces 5methylcytosine (m5C) residues in DNA sequences such as CG, CNG, and CNN. Adenine DNAmethylation also occurs in plants. The resulting m5C residues in DNA substantially affect the interaction ofDNA with different proteins, including regulatory proteins. DNA methylation often prevents DNA bindingto such proteins and inhibits gene transcription, but sometimes it is required for binding to other regulatoryproteins. Specific m5CpG DNAbinding proteins were described. The binding of such proteins to DNAorchestrates the whole protein ensemble of the transcription machinery and induces its activity. Thus, DNAmethylation can serve as a signal of positive and negative control for gene activities. DNA methylation ineukaryotes is species and tissuespecific. It is regulated by hormones, changes with age, and is one of themechanisms controlling cellular and sex differentiation. DNA methylation controls all genetic processes:DNA replication, repair, recombination, transcription, etc. Distortions in DNA methylation and other epigenetic signals cause premature aging, cancer, diabetes, asthma, severe mental dysfunctions, etc. Changes inthe DNA methylation profile accompany carcinogenesis and are a reliable diagnostic marker of various typesof cancer even at the early stages of tumorigenesis. Epigenetic parameters are very important for understanding the somaclonal variation mechanisms; characterization of clones and cell cultures, including stem cellsat various differentiation stages; and determination of their differentiation directions. Directed change in theDNA methylation profile is an efficient biotechnological tool for activation of transcription of seed storageprotein genes in cereals and it is used, in particular, for an inheritable increase in protein content in wheatgrain. The inhibitor of DNA methylation with 5azacytidine is used for treatment of skin cancer. Various regulators of enzymatic modifications of histones are already used in clinical practice for the treatment of somehuman and animal diseases. The use of specific small RNAs in the therapy of cancer and other diseasesappears to be particularly promising, especially in connection with directed inhibition of transcription of thegenes responsible for cell malignization and metastasis. The therapeutic effect of many small biologicallyactive peptides can be largely determined by their action at the epigenetic level. Thus, the phenotype is theproduct of combined realization of the genome and epigenome. In this regard, P. Medawars wellknownexpression genetics supposes, epigenetics disposes sounds quite correct and very impressive. Epigenetics isa quickly developing and very promising science of the 21st century that is already ingrained in biotechnologies, medicine, and agriculture.
Keywords: apoptosis, histone, DNA methyltransferase, DNAbinding proteins, genomics, genosystematics,gene silencing, cell differentiation, DNA methylation, mitochondria, development, replication, cancer, aging,transcription, chromatin, evolution, endonucleases, epigenetics, 5methylcytosine, N6methyladenine
RUSSIAN JOURNAL OF GENETICS: APPLIED RESEARCH Vol. 4 No. 3 2014
EPIGENETICS TODAY AND TOMORROW 169
as a field of knowledge explaining how and why cells(organisms) with an identical genotype can differ ininheritable phenotype. Others (e.g., D. Gotchling andA. Riggs), describe epigenetics as the science of heritable changes that are not associated with mutations inthe DNA itself. S. Ellis defines epigenetics as inheritedcellular memory associated with structural changesin chromatin. This definition, though too general andvague, is in fact correct, because many things in ontogeny are ultimately determined by the modulations ofthe chromatin structure. Renowned geneticist RobinHolliday considers epigenetics as the study of thecontrol of gene activity in space and time in the courseof development of complex organisms. He is amongthe first to point out the possible biochemical nature(DNA methylation) of heritable epigenetic signals.These signals accompany and are often crucial duringthe realization of genetic information. Epigenetics isconsidered as a set of knowledge about changes in genetranscription as a result of the modulation of chromatin organization without changing the DNA sequence.In principle, perhaps, this would be enough. I wouldonly like to add that epigenetics is the science of heritable properties of the organism that are not associatedwith changes in the DNA nucleotide sequence but canbe indirectly encoded in the genome. This rapidlydeveloping field of knowledge has already gained itsfooting, turned into an independent science, and issubstantially ingrained in modern biotechnology andmedicine. The epigenetic phenomena also include, inparticular, the phenomenon of lysogeny in bacteriophages, the socalled gene position effect in Drosophila, prion diseases, X chromosome inactivation insexual differentiation in animals, etc. Anyway, even atthe early stages of its inception, epigenetics was associated with chromatin reorganization (remodeling,rearrangements) and modifications of chromatin proteins, including histones. In 1930, H. Muller describedmutations in Drosophila, which led to a change in phenotype and were caused by movement rather thanchange in genesrearrangement of chromosomes(eversporting displacements). Thus, the activity of agene depends on its position in the genome, chromosome, and chromatin.
The classic studies of Nobel laureate John Gurdonon the transplantation of nuclei into fertilized anuclear Xenopus eggs showed that the realization ofgenetic information of nuclear DNA (nDNA) andembryo development are not associated with anymutations in nDNA but are triggered and controlledby some competent epigenetic elements (signals) in thecytoplasm. Interestingly, the siliation pattern of in theprotozoan Paramecium is transmitted clonally. It wasestablished that transposons can determine the geneexpression profile in somatic cells. On the other hand,the great diversity of antibodies is mainly due to DNArearrangements in somatic cells. In 1975, Arthur Riggsand R. Holliday reported that X chromosome inactivation and, consequently, sexual differentiation in
mammals is associated with DNA methylation. InRussia, tissue (cell) heterogeneity of DNA methylation was discovered and the idea that DNA methylation is a mechanism of regulation of gene expressionand cell differentiation was formulated (Vanyushinet al., 1970). In fact, it was the first material chemically identified and interpreted epigenetic signal.Today, the idea of the epigenome has appeared, and itis clear that the phenotype is the product of combinedrealization of the genome and epigenome. The concept and term epimutations are already entered into theuse. Along with genetic diseases, there exist epigeneticdiseases. Abnormalities in the epigenome cause cancer, diabetes, asthma, and many mental and other disorders. Of course, this largely depends on the environment. The socalled epigenetic profile of the body isthe basis for creating the digital pathology. Epigenomesignificantly changes with age. In particular, we discovered the age specificity of DNA methylation. Furthermore, according to our understanding, epimutations caused by DNA methylation may underlie programmed aging and determine the lifespan.Fundamental epigenetic studies have changed ourunderstanding of the genetic identity of homozygoustwins and clones of plants and animals. It was foundthat they can significantly differ in epigenetic profiles.Somaclonal variation is often largely determined bythe changes in epigenetic parameters and signals.
Despite the great advances in molecular biologyand molecular genetics in the last century, manyimportant problems of general biological significanceremain unsolved.