Epigenetics today and tomorrow

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<ul><li><p>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.</p><p>168</p><p>INTRODUCTION</p><p>Genetics proposes, epigenetics disposes</p><p>Peter Medawar, Nobel laureate</p><p>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</p><p>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</p><p>Epigenetics Today and TomorrowB. F. Vanyushin</p><p>Belozersky Institute of Physicochemical Biology, Moscow State University, Moscow, 119992 Russiaemail: vanyush@belozersky.msu.ru</p><p>Received June 3, 2013; in final form, November 1, 2013</p><p>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.</p><p>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</p><p>DOI: 10.1134/S2079059714030083</p></li><li><p>RUSSIAN JOURNAL OF GENETICS: APPLIED RESEARCH Vol. 4 No. 3 2014</p><p>EPIGENETICS TODAY AND TOMORROW 169</p><p>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.</p><p>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</p><p>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.</p><p>Despite the great advances in molecular biologyand molecular genetics in the last century, manyimportant problems of general biological significanceremain unsolved. Among them, the most importantare cell differentiation and gene activity regulation. Westill do not understand completely how the normaldevelopment of the organism proceeds and how cellswith initially the same genetic information make theirown (different) ways during development, with accurate and correct realization in space and time of specific regions of the genome to form a specific phenotype. How does the cell decides when it is time todivide and differentiate? Epigenetics offers a new wayto look at these issues and find a solution to burningmysteries of biology, such as cell identity (specificity),carcinogenesis, stem cell plasticity, regeneration ofanimal and plant cells and tissues, aging, and programmed cell death.</p><p>Epigenetics is often recalled when the effect of theenvironment on gene expression (diet, hormones, andother factors and environmental conditions) are considered. Epigenetics represents a new comprehensiveand promising horizon of our knowledge in the postgenomic era. Indeed, we inherit something more thanjust the sum of the genes and, according to Nobel laureate D. Watson, something else besides the DNAsequences. All this emphasizes once again that, without epigenetics, it is impossible to solve the main problem of biologyto establish the driving mechanismsof regulation of gene expression and cell differentiation under different environmental conditions.</p></li><li><p>170</p><p>RUSSIAN JOURNAL OF GENETICS: APPLIED RESEARCH Vol. 4 No. 3 2014</p><p>VANYUSHIN</p><p>In humans, genetic information is written in23 pairs of chromosomes comprising approximately25000 genes. The human genome contains approximately 3 109 base pairs, or 1 107 nucleosomes. Thelength of DNA in higher eukaryotes is about 2 m, andit is condensed in the nucleus by a factor of approximately 10000. As much as approximately 96% of themammalian genome is represented by noncoding andrepetitive DNA sequences. There is a great diversity ofnumerous elements and factors for regulating geneexpression, such as DNA binding to different proteins,including the regulatory ones; proteins methylCpGDNAbinding and other proteins; different modifications of histones; nucleosome remodeling and chromatin rearrangement in general; and hormonereceptor complexes, DNA methylation, and interaction with short noncoding RNAs. Gene expressionrequires large complex systems and assemblies of morethan 100 proteins involved in transcription initiationand elongation from one promoter and in messengerRNA processing. Most likely, a transcriptioncompetent gene state cannot be ensured by only one trigger(e.g., a particular protein modification) and requiresthe sum and cumulative effect of many factors to create a proper active epigenetic state in a certain chromatin region. Epigenetic control can promote(enhance) the primary signal (promoter stimulation)or mediate gene silencing. Epigenetic memory is oftenassociated with specific histone modifications in chromatin. This unique chromatin configuration apparently can be transmitted from cell to cell in a series ofcell divisions. In particular, this can be observed ingene silencing, and this ban (conformational lock)in a particular chromosomal region can become evenstronger and more significant as a result of additionalDNA methylation induced (permitted) by this chromatin state. In this case, DNA itself can be consideredas a selforganizing polymer with an ordered structurein chromatin, able to respond and perceive differentepigenetic signals.</p><p>Environmental factors can markedly affect theactivity of enzymes (and their cofactors) performingmodifications of histones and DNA. Such cofactorsinclude ATP for kinases, acetyl coenzyme A for acetylases, and SadenosylLmethionine (SAM) for various methyltransferases. Of course, the content of thesecofactors in the cell may significantly vary and dependon the environment, including the diet. An adequateepigenetic control in the cell is based on the balance ofmany factors, which is not always accurately transmitted during cell division. In view of this, an importantquestion arises as to how information about the chromatin structure is transmitted from the maternal cellto the daughter cells. In principle, this could take placeas follows. It is known that the synthesis of core histone proteins is strictly regulated in the cell cycle. Thetranscription of the genes encoding these proteinstakes place in the S phase of the cell cycle and is wellcoordinated with the nDNA replication. Upon the</p><p>assembly of the newly formed chromatin, its specificproteins, depending on the degree and nature of theirenzymatic modifications, may or may not bind toDNA to form sites inaccessible or accessible, respectively, for transcription. In this process, DNA againserves as a selforganizing matrix. Recently it wasestablished that mutations in the genes encoding theenzymes involved in histone modifications lead tonucleosome remodeling and are accompanied byimpaired development of organisms and neoplasia.The development of tumors in the mutant mice withthis pathology was traditionally attributed to the category of genetic diseases. In fact, the changes in...</p></li></ul>