Epigenetics

Genetics proposes;epigenetics disposes

Peter B. Medawar

Not genes rule man, but man - genes

Epigenetics is a field of genetics that studies the mechanisms of heredity and variability,DOES NOT change the primary sequence of DNA and RNA.S.G. Inge-Vechtomov, 2004

Epigenetic regulation is a process that leads to a change in the activity of a gene without changes in its coding sequence, which stably inherits after the disappearance of the factor that caused this change.

Epigenetics is "the study of mechanisms controlling the activity of genesin the development of organisms."Robin Holliday

Epigenetics studies changes in gene expression caused by mechanismsthat, by definition, should not be associated with changes in thesequence of DNA nucleotides (changes in the structure ofimmunoglobulin genes are an exception to this rule).

The term "epigenetics" (from the Greek epi-over, above, external) wasproposed by Conrad Hal Waddington in 1942 to describe the interaction ofgenes with their environment during the formation of the phenotype.

Epigenesis - the theory of embryonic development of organisms, duringwhich occurs successive neoplasms of organs.Epigenetics - believed that in the process of ontogeny occursneoplasm of structures and organs of the embryo from the structurelesssubstance.V. Garvey "Studies on the Birth of Animals" (1651)

Epigenetic theory of evolution (ETE) - one of the modern evolutionary theories, based on epigenetics data. The main provisions of the epigenetic theory of evolution were formulated in 1987 by MA Shishkin on the basis of ideasI. I. Shmalhausen and K. H. Waddington. As the main substratum of natural selection, the theory considers an integral phenotype.In accordance with this theory, the selection not only fixes useful changes, but also takes part in their creation.

Воронов Л.Н., Козлов В.А. Создание новой концепции эволюции // В сборнике: Наука и инновации-2013 Материалы Восьмой международной научной школы. 2013. С. 151-165.

5 most significant discoveries in epigenetics5 DNA - not responsible for everything.Supervisory functions belong to the epigenome.Epigenus controls the top of the genome with each gene through epigenetic markers. The behavior of genes can be transmitted without changing the genetic code - the same code can be read in different ways depending on the environmental conditions of the environment [John Cloud].Chess twins.

4 In the development of diseases, the greater part is played by the epigenome.The expression of epigenetic changes in later life can be the cause of age-related diseases, such as Alzheimer's."With age, our genes also age, so they can just shut down, which leads to illness," Sarah Baldauf said. Epigenetic changes can be regulated by medications.

https://www.ohio.edu/plantbio/staff/showalte/PBIO%203300%20&%205300/Epigenetics,%20DNA%20How%20You%20Can%20Change%20Your%20Genes,%20Destiny%20--%20Printout%20--%20TIME.pdf

Sarah Baldauf Epigenetics Finds That Our Genes Are Not the Whole Story. Researchers are looking at how chemical changes can affect our DNA – and disease risk // Health care. 2010. http://health.usnews.com/health-news/managing-your-healthcare/research/articles/2010/01/08/epigenetics-finds-that-our-genes-are-not-the-whole-story

3 Epigenetics is closely related to the development of cancerChanges in the epigenome cause tumor growth.Cancer is associated with mutations.BUT, tumors can grow because normal cells with excellent protection receive an epigenetic signal not to do their job, this regulation can be suppressed by drugs.With the help of certain food products such as broccoli, it was possible to "turn off" the work of proteins that develop in the human body along with cancer and do not allow cancer cells to die naturally - Roderick Dashwood (Roderick Dashwood).

Sulforaphane cruciferous

Myzak M.C., Karplus P.A., Chung F.L., Dashwood R.H. A novel mechanism of chemoprotection by sulforaphane: inhibition of histone deacetylase // Cancer Res. 2004. Vol. 64, No 16. P. 5767-6774.

5 most significant discoveries in epigenetics

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2 Antenatal care is necessary to follow upfor epigenetic changes

What happens if a pregnant rat is exposed to insecticides and fungicides? Will this affect her offspring? During the study, during this exposure, epigenetic changes occurred that led to an increase in male infertility or contributed to a very low production of sperm. These epigenetic changes have been preserved for the next four (!) Generations.Malnutrition is especially dangerous in the first 10 weeks of pregnancy.

E. W. Tobi, R. C. Slieker, A. D. Stein, H. E. D. Suchiman, P. E. Slagboom, E. W. van Zwet, B. T. Heijmans, L. Lumey. Early gestation as the critical time-window for changes in the prenatal environment to affect the adult human blood methylome. International Journal of Epidemiology, 2015; DOI:10.1093/ije/dyv043

5 most significant discoveries in epigenetics

1 Epigenetics is associated not only with ecology, but also with social interactions

The behavior of toddlers in the future and their epigenetic markers depend on how the rat cares for their cubs.Lack of care can be corrected with the help of special medications that change the epigenetic background.As for people, when stressful situations occur in their lives, they also leave their imprint on how our genome behaves.In addition, epigenetic changes persist even after the stress hormone leaves our body.

Georgia E Hodes Sex, stress, and epigenetics: regulation of behavior in animal models of mood disorders // Biology of Sex Differences. 2013. 4:1DOI: 10.1186/2042-6410-4-1

5 most significant discoveries in epigenetics

Damage to DNA can be corrected:

sulforaphane (found in broccoli);Curcumin (turmeric in the composition);epigallocatechin-3-gallate (green tea);resveratrol (found in grapes and wine).

Lack of sleep during the week adversely affects the activity of more than 700 genes.The expression of 117 genes is positively influenced by sports training.

Levels of epigenetic regulation

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1. DNA (genome) methylation,repetitive sequences, mutations of distant regulatory elements, transpositions of genetic material

2. RNA (transcriptome) regulatory motifs of pre-mRNA, antisense RNA, untranslated RNA,micro RNA,double-stranded RNA

3. Proteins (proteom) methylation / demethylation of lysine 4 and 9 histone H3, acetylation / deacetylation of histones

Genetic

As a rule, irreversible (mutations) Changes in the primary structure of DNA Stable inherited

Epigenetic

As a rule, reversible Do not affect the changes

in the primary structure of DNA

There are long-term and short-term

Many interrelated mechanisms

Changes

Epigenetic modifications

Modifications of DNA

Modifications of histones

Modifications of non-histone chromatin proteins

Change the status of transcription

Cell somatic

Placement of markers along DNA causes an epigenetic process

Placement of markers along DNA

causes an epigenetic process

Mitosis

Expression mode saved

Expression mode saved

Gamete with the necessary

markers

GametogenesisGamete with the necessary

markers

Zygote with a part of the

markers

Epigenetic changes occur at the signal, remain in a series of cellular mitotic divisions, and can be transmitted to the next generations of cells and even multicellular organisms

Signal

Genetic bookmarking

Transvection

Epigeneticprocesses

InactivationX chromosomes Maternal effects

Paramutation

Genomic Imprinting

Reprogramming

Effect of position

RNA interference

Suppression of transposons

Cells differentiation

Development of the organism of an alternative path

Epigenetic processes begin with the arrangement ofepigenetic markers, the aggregate of which forms anepigenetic

Epigenum - the aggregate of all epigenetic markers that cause theexpression of genes in a given cell

As epigenetic markers that affect the triggering of transcription, there can be DNA methylation and histone acetylation.

If the start of transcription has already occurred, then further types ofregulatory RNAs can serve as markers.

Under the influence of theenvironment, the epigen can varythroughout the ontogenesis.

Epigenetic drift is the age-related changein gene expression.

Epigenetic markers - persistent, including inherited change in the genome as a whole: for DNA this is methylation;for histones this is: acetylation, phosphorylation, methylation, glycosylation, ubiquitinylation, sumoylation for chromatin in general, it is remodeling and post-transcriptional

regulation with the help of microRNA.

Epigenetic modifications of DNA and histones. Me - methyl group, Ac - acetyl, P - phosphoric acid residue, SUMO - Small Ubiquitin-like Modifier (ubiquitin-like modifying protein).

Лапская Ю. Пилюли для эпигенома http://biomolecula.ru/content/1355

Influence of plants on epigenetic processes

Modifications of histones

DNA metalation

Epigenetic modifications of DNA and histones

Methylation of DNA

http://www.ks.uiuc.edu/Research/methylation/

http://my.science.ua/blog/epigenetika--mehanizm-dejstvija.html

The process of DNA methylation is the addition of a methyl group to the cytosine at the C5 position of the cytosine ring.The DNA methylation process in mammals has four enzymes called DNA methyltransferases (Dnmts).

Methylation occurs usually in those places where near the cytidyl nucleotide is guanylic, i.e. in the CG dinucleotide.

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In particular, proteins that recognize methylated bases are attached toDNA due to the presence of special methyl-CG-binding domains in them.There are 4 types of such proteins: МеСР2, MBD1, MBD2 и MBD3.

http://wsyakayawsyachina.narod.ru/chemistry/apygenetics.html

Methylation ofcytosine residuesstabilizes the DNAhelix and affects itsinteraction withproteins.

The promoter of the gene is not methylated, transcription can go

http://www.ncc.go.jp/en/nccri/divisions/14carc/14carc01_1.html

В большинстве случаев метилирование промоторных областей гена приводит к подавлению его активности.

It is obvious that different genes are methylated in cells with differentspecializations.

CG methylatedCG non methylated

Expression of the gene is impossible, since methylated promoter

Demethylation Additional methylation de novo

DNA replication

The new (red) chain is methylated according to

the sample of the original

A methyl group can be removed, a new one can be added, it can be replicated with DNA replication.

Since the pattern (methylation pattern) is copied in the newly synthesized chain, the daughter cells get DNA methylated in the same manner as the mother cell.

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Demethylation in the promoter regionmost often results in its release fromthe blocking proteins and in activationof the transcription of thecorresponding gene.

Ming Zhu Fang and her colleagues at Rutgers University (New Jersey,USA) found that in adults, with the help of epigallocatechin gallate - iscontained in green tea leaves - due to DNA demethylation, tumorsuppressor genes can be activated.

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Histone modification is the second most important epigenetic type ofmarkers affecting transcription

More than 50 different modifications of histone proteins have beendetected, which have different effects on gene expression. The template forthe modification of proteins began to be called the histone code. These arepost-translational modifications of amino acid residues of histones at the N-terminal end. Regulation of gene expression using a histone code is muchmore labile than with DNA methylation.

The main methods of covalent modification of histone proteins

N-terminal regions of the molecule that extend beyond the nucleosome

acetylation methylation phosphorilation

Type 2: remodeling chromatin structure with ATP-dependent chromatinremodeling proteins.

ubiquitization

Type 1:

Structure of histones

The molecule of each histone consists of a central structured three-helical domain (one long and two short alpha-helical segments connected by a loop segment) and unstructured N-terminal "tails".

Acetylation of histones is the attachment of an acetyl group to a lysine that is located at the free end of one of the histones that make up the nucleosome. David Ellis, 1996Most often, such acetylation activates the work of the gene, but such a strictly defined dependence may not be.

Deacetylation of histones, in particular H4, is an important component of the mechanism of repression. It remodels the structure of chromatin, most often increasing the degree of its compaction, which leads to repression of transcription.

Ubiquitination is the post-translational addition of one or more ubiquitin monomers with ubiquitin ligases by a covalent bond to the side amino groups of the target protein.The addition of ubiquitin influences the localization and function of proteins. The very first discovery was the degradation of proteins labeled with multubiquitin chains.In 2004 A. Chekhanover, A. Hershko and I. Rose were awarded the Nobel Prize in Chemistry "for the discovery of ubiquitin-mediated protein degradation."

The structure of the nucleosome is a repeating unit of chromatin

Histones are always formed by 146 pairs of nucleotides

Core histones DNA

Histone modifications

For delivery to the chromatin of histonesand for proper nucleosome assembly,various histone chaperones are used;their work affects the functional state ofthe chromatin.ATP-dependent chromatin-remodelingproteins modify the structure ofchromatin, changing DNA-histone-newcontacts. Modifications of chromate-tincan be different:nucleosomes can be reassembled in thechromatin composition or removed, theposition of the nucleosome relative to theDNA sequence can be changed. All thesemodifications affect the activity of genes.

Histone modifications affect: Regulation of gene expression Maintenance of chromatin structures Cell differentiation X chromosome inactivation in mammals Carcinogenesis The course of various genetic diseases Aging DNA repair Transcription Replication and segregation

2nd type Remodeling with ATP-dependent chromatin remodelingproteins is a change in the binding of DNA to histones.

Type 3 - different types of RNA

Epigenetic markers in the form of molecules of microRNAs and other types ofregulatory RNA can be transferred to the next generation along with nuclear DNAor in a free form through the cytoplasm of gametes.

Examples are described where a parent RNA, read from a mutant copy of the gene,enters the fertilized egg. This RNA modifies the process of transcription of the"healthy" gene or the subsequent maturation of the RNAs read from it, so that thephenotype is mutant as a result. Such an RNA can increase the number of itscopies by the prion protein principle.

In 2011, it was shown that methylation of mRNA plays a role in predispositionto diabetes, which gave rise to a new area of study of RNA-epigenetics.

RNA switches

gene

promotor4

3`5`

5`3`1 2

transcription unitterminator

part of a gene encoding a polypeptide

3

From section 2 of the transcription unit, the RNA switch is first synthesizedand immediately collapses into a definite three-dimensional structure, theconfiguration of which may change as a result of interaction with anymolecule-a signal substance. Changing the configuration of the RNA switchwill affect the continuation of the transcription of the gene, and this effectcan be either activating or suppressive.The signaling substance can be, for example, a polypeptide encoded by thegene; in this case there will be a classical regulation on the type offeedback.RNA switches realize the ancient mechanism of regulation, which isfound in archaea, eubacteria, eukaryotes - the legacy of the RNA world.

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