Epigenetics

Histone modification

- known to play critical role in chromatin packaging and gene expression (Book: Environmental Epigenetics Source: Jenuwein T, Allis CD (2001) Translating the histone code. Science 293 (5532):1074-1080) -commonly known epigenetic modification - a complex of DNA and globular proteins (Histones) package heritable genetic information in eukaryotic nuclei in form of nucleosomes (constitute chromatin) -Nucleosomes composed of 147 bp of DNA wrapped around core histone proteins (H2A,H2B,H3,and H4) -additional Histone (H1) located at outer surface of nucleosome to anchor DNA to nucleosome -H3 and H4 have long tails (extend out from nucleosome (can be modified chemically by acetylation,methylation, ubiquitination,phosphorylation, sumoylation, citrullination, and ADP-ribosylation )) (Book: Environmental Epigenetics Source: Baccelli A, Bollati V (2009) Epigenetics and environmental chemicals. Curr Opin Pediatr 21(2):243-251) -chemical modifications can result in closed chromatin conformation that suppresses transcription, or in an open conformation that activates transcription -most common modifications are acetylation, and methylation on histone lysin residues -increased acetylation -> transcription activation -methylation of histones -> either repression or activation of transcription as determined by the lysine residue position involved (Book: Environmental Epigenetics Source: Bollati V, Baccarelli A (2010) Environmental epigenetics. Heredity 105(1): 105-112)

Epigenome

-DNA is wrapped around histones both DNA and -histones covered with chemical tags -this second layer of structure called epigenome -epigenome shapes physical structure of genome -tightly wraps inactive genes-> un readable -relaxes active genes -> easily accessible -different set of genes active in different cell types - While DNA code is fixed for life epigenome remains flexible (allows us to adjust to changes in the world around us and to learn from experiences) -flexibility also important for forming new memories - epigenetic tags react to signals from the outside world (e.g. diet, stress) -epigenome adjusts specific genes in our genomic landscape in response to rapid changing environment (APA format: Genetic Science Learning Center (2014, June 22) The Epigenome at a Glance. Learn.Genetics. Retrieved December 27, 2015, from http://learn.genetics.utah.edu/content/epigenetics/intro/ MLA format: Genetic Science Learning Center. "The Epigenome at a Glance." Learn.Genetics 27 December 2015 <http://learn.genetics.utah.edu/content/epigenetics/intro/> Chicago format: Genetic Science Learning Center, "The Epigenome at a Glance," Learn.Genetics, 22 June 2014, <http://learn.genetics.utah.edu/content/epigenetics/intro/> (27 December 2015)) -combination of structure and function of genome= epigenome -consists of different territories localized at defined areas of the interphase nucleus (each of them divided into domains the smallest entities of which are the genes (Book: Epigenetic Territory and Cancer Source: Haaf T, Schmid M (1991) Chromosome topology in mammalian interphase nuclei. Exp Cell Res 192:325-332) -reveals different types of chromatin condensation and their special arrangements are of high relevance (cell type investigated as well as age of cell have to be taken into consideration) -in euchromatic region epigenome influences replication , transcription and repair mechanisms (book: Epigenetic Territory and Cancer Source: Cremer T (2010) Von der Genetik zur Epigenetik und Epigenomforschung—Essay zur Geschichte der Vererbungsforschung und zur Zukunft der prädiktiven Medizin. In: Doerfler W, Ulrich HG, Böhm P (eds) Medicine at the interface between science and ethics, Nova Acta Leopoldina, Bd 98. Deutsche Akademie der Naturforscher Leopoldina, Halle pp 87-165) -in course of the life cycle of a cell the epigenome passes through a number of alterations (as structure of nucleus is in tight connection with its function each change in structure has influence on its function

Mechanisms of Epigenetics

-Epigenetic signatures provide best explanation for how one genotype can be translated into many different phenotypes -Example: series of studies showed that alternation in DNA methylation led to changes in coat color in Agouti mice (Book: Environmental Epigenetics Source: Michaud EJ et al (1994) Differential expression of a new dominant agouti allele (Aiapy) is correlated with methylation state and is influenced by parental lineage. Genes Dev 8(12):1463-1472 Also: Dolinoy DC, Huang D, Jirtle RL (2007a) Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc Natl Acad Sci U S A 104(32):13056-13061 Also: Dolinoy DC, Weidman JR, Jirtle RL (2007b) Epigenetic gene regulation: linking early developmental environment to adult disease. Reprod Toxicol 23(3):297-307) -Numerous experiments have demonstrated the importance of epigenetics -Studies involving monozygotic (MZ) twins show that each individual develops different disease susceptibilities with age and may be in part explained by epigenetic modifications since these diverge as MZ twin age (Book: Environmental Epigenetics Source: Fraga MF et al (2005a) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A 102(30):10604-10609) -Global DNA methylation, global Histone H3 and H4 acetylation and sequence-specific DNA methylation were examined followed by relative one expression profiles (showed little differences in young twins but significant alterations in aged twins) -for any of the methods of gene regulation, absence of the protein product of the gene causes a change in the function or development of the cell (Book: Epigenetics explained Source:„Nova Science in the news, Epigenetics - beyond genes, http://www.science.org.au/nova/098/098key.htm, 29 May 2010." Auszug aus: Janine Schott. „Epigenetics explained." iBooks. https://itun.es/de/KxhUz.l) -epigenetic processes regulate gene expression and thereby cell differentiation in the process of embryogenesis but also in the postnatal periods -also cause abnormalities in higher age -gene regulation processes can only proceed correctly if transcription occurs at right time in a defined gene locus epigenetic gene regulation can reveal DNA packing which is inherited over a high number of cell divisions in the different somatic cell systems -both somatic/germ cells can develop alterations of epigenetic pattern (can inherit these changes to offspring) (Book: Epigenetic Territory and Cancer pg. 20) -cellular differentiation in multicellular organisms based on fine-tuned expression of thousands of genes -cell specific regulation mechanisms of gene expression needed b/c nearly all cells in organism carry same genetic content but different cellular functions are displayed -epigenetic processes play key role in these complex mechanisms (b/c they control packaging and function of chromatin and regulate gene expression without changing DNA sequence itself) -on molecular level, epigenetic regulation includes specific patterns of DNA methylation, chromatin structure, and by post-translational histone modifications (acetylation, ubiquitylation,phosphorylation, and methylation, non- coding RNAs (ncRNAs) (book: Epigenetic Territory and Cancer for review: -Delaval K, Wagschal A, Feil R (2006) Epigenetic deregulation of imprinting in congenital diseases of aberrant growth. Bioessays 28:453-459 -Kacem S, Feil R (2009) Chromatin mechanisms in genomic imprinting. Mamm Genome 20:544-556 -Tollefsbol T (ed) (2011) Handbook of epigenetics. The new molecular and medical genetics. Elsevier, Amsterdam) -DNA methylation one major from of epigenetic modification

Imprinted genes

-Imprinted genes are genes whose expression is determined by the parent that contributed them. -Imprinted genes violate the usual rule of inheritance that both alleles in a heterozygote are equally expressed. -genomic imprinting i.e. the parent-of-origin expression of gene-copies -describes an epigenetic marking of specific genes that allows expression from only one of the two parental alleles (for review: Reik W, Walter J (2001) Genomic imprinting: parental influence on the genome. Nat Rev Genet 2:21-32) -inborn imprinting markers are clustered and approx. 60 imprinted clusters/gene regions have been estimated in the human genome but probably there are much more (for review: Horsthemke B (2010) Mechanisms of imprint dysregulation. Am J Med Genet C Semin Med Genet 154C:321-328) imprinting marks inherited from parental gametes and then maintained in the somatic cells of an individual -their programming is subject to a so-called "imprinting" cycle during life (leads to a reprogramming at each generation) -during early development , methylation of genome runs through dramatic changes and is linked to the rapid differentiation and formation of the various tissues and organs -imprinted marks are erased in the germ-line and re-established according to the sex of contributing parent for next generation (Book: Epigenetic Territory and Cancer ) -Epigenetic imprints are stable marks in the genome (control gene expression and are established during ontogenesis during cell division and cell differentiation (Book: Epigenetic Territory and Cancer Source: Varrault A, Gueydan C, Delalbre A, Bellmann A, Houssami S, Aknin C et al (2006) Zac1 regulates an imprinted gene network critically involved in the control of embryonic growth. Dev Cell 11:711-722) -normal embryonic development requires balanced maternal+paternal contribution to genome of zygote - for imprinted genes either maternal or paternal copy is methylated/unmethylated-> active/inactive (if one of these gens or chromosomal regions has been inherited only from one parent, normal development of embryo not possible) (Book: Epigenetic territory and Cancer) -imprinting is process in which genes are silenced, depending on whether they are maternal or paternal in origin -epigenome cycles through series of precisely timed methylation changes (designed to ensure proper development, both in utero and throughout life, of the organism) (Book: Environmental Epigenetics)

Loss of imprinting

-In humans, paternal genome actively demethylated, maternal genome passively demethylated following fertilization (Book: Environmental Epigenetics Source: Bernal AJ, Jirtle RL (2010) Epigenomic disruption: the effects of early developmental exposures. Birth Defects Res A Clin Mol Teratol 88(10):938-944) - Genomic imprinting results in parent-of-origin-dependent monoallelic expression of a subset of critical autosomal genes (Book: Environmental Epigenetics Source: Murphy SK, Jirtle RL (2003) Imprinting evolution and the price of silence. Bioessays 25(6):577-588) -loss of methylation can either shut down these critical genes or lead to overexpression of gene product -b/c of their monoallelic expression, imprinted genes are particularly susceptible to dysregualted expression that results from epigenetic aberrations -Environmental exposures (alter imprinting of these genes) will lead to enhanced susceptibility to disease (Book: Environmental Epigenetics Source: Das R, Hampton DD, Jirtle RL (2009) Imprinting evolution and human health. Mamm Genome 20(9-10):563-572) -e.g. study showed that loss of imprinting at insulin-like growth factor 2 (IGF2) locus could be induced by synthetic methyl-donor-deficient post weaning diet in mice (Book: Environmental Epigenetics Source: Waterland RA et al (2006) Post-weaning diet affects genomic imprinting at the insulin-like growth factor 2 (Igf2) locus. Hum Mol Genet 15(5):705-716)

Epigenetics and the Environment

-both environment and individual lifestyle can directly interact with genome to influence epigenetic stage (changes my be reflected at various stages throughout a person's life and even later in generations) - human epidemiological studies have provided evidence that prenatal and early postnatal environmental factors influence the adult risk of developing various chronic diseases and behavioral disorders -studies have shown that children born during period of Dutch famine (1944-1945) have increased rates of coronary heart disease and obesity after maternal exposure to famine during early pregnancy compared to those not exposed to famine -> less DNA methylation of the insulin.like growth factor II (IGF2) gene (a well-characterized epigenetic locus) found to be a associated with his exposure Sources used by http://www.whatisepigenetics.com/fundamentals/2/: 1.Jirtle R.L. and Skinner M.K. Environmental epigenomics and disease susceptibility. Nature Reviews Genetics 8, 253-262 (2007). ↩ Painter R.C., Roseboom T.J., Bleker O.P. Prenatal exposure to the Dutch famine and disease in later life: an overview. Reproductive Toxicology 20, 345-52 (2005). ↩ Heijmans B. T., Tobi E. L., Stein A. D., Putter H., Blauw G. J., Susser E.S., Slagboom P. E., and Lumeye L.H. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci USA 105(44): 17046-17049 (2008).

Definition /General

-carefully orchestrated chemical reactions activate and deactivate parts of the genome (at strategic times and in specific locations -Epigenetics = study of these chemical reactions and the factors that influence them (APA format: Genetic Science Learning Center (2014, June 22) Epigenetics. Learn.Genetics. Retrieved December 27, 2015, from http://learn.genetics.utah.edu/content/epigenetics/ MLA format: Genetic Science Learning Center. "Epigenetics." Learn.Genetics 27 December 2015 <http://learn.genetics.utah.edu/content/epigenetics/> Chicago format: Genetic Science Learning Center, "Epigenetics," Learn.Genetics, 22 June 2014, <http://learn.genetics.utah.edu/content/epigenetics/> (27 December 2015) -term refers to heritable changes in gene expression (active vs inactive genes)-> changes do not change the underlying DNA sequence -epigenetic change is regular and a natural occurrence but can be influenced by several factors (e.g. age, environment/lifestyle, disease state) - epigenetic changes can be both harmless (e.g. manner in which cells terminally differentiate to end up as for example skin cells) and harmful (e.g. cancer) -DNA methylation, histone modification and non-coding RNA- associated gene silencing are considered to initiate epigenetic change http://www.whatisepigenetics.com/fundamentals/ -Epigenetics involves genetic control by factors other than an individual's DNA sequence -changes can switch genes on or off and determine which proteins are transcribed -involved in many normal cellular processes -cells, tissues, and organs differ bc they have certain sets of gens expressed and others that are inhibited (Epigenetic silencing one way to turn genes off) -epigenetics also important for X-chromosome inactivation in female mammals (necessary so that females don't have twice the number of X-chromosome gene products as males (source http://www.nature.com/scitable/topicpage/epigenetic-influences-and-disease-895 used: Egger, G., et al. Epigenetics in human disease and prospects for epigenetic therapy. Nature 429, 457-463 (2004) doi:10.1038/nature02625) -epigenetics focuses on how much and when gene expression occurred, without changing gene sequence (book: environmental epigenetics- source: Esteller M (2006) The necessity of a human epigenome project. Carcinogenesis 27(6): 1121-1125) -"gene expression regulatory machinery" like a signature or switch imprinted in the gene sequence (is beyond the normal genetic coding A-T-G-C and is functioned like the 5th genetic code- can not only initiate gene expression but also be passed down to next generation) -may researchers trying to find the "changes" when gene expression is altered without change in DNA sequence -Forms of Epigenetic Modifications: DNA methylation, histone modifications, RNA interference, chromosomal instability, transposons, and loss of imprinting (book:Environmental Epigenetics Source: Su LJ et al (2011) Epigenetic contributions to the relationship between cancer and dietary intake of nutrients, bioactive food components, and environmental toxicants. Front Genet 2:91) - Epigenetics can be regarded as comparatively new branch of genetics -Epi =prefix taken from Greek meaning "added on"-> epigenetics = added onto the genes -may be defined as the study of heritable and reversible changes in genes induced by environmental entities, including nutritional factors (experience can switch genes on or off and this modification is inherited by future offspring) -Existing research has investigated stressful events, the response to that stress and its heritability (includes the stress that results from insufficient food, different types of food, too much food, and nutritionally poor foods) -> evidence available comes from invention of a multitude of diseases that modern humans have developed since introduction of agriculture (Book: Epigenetics explained Source:„Lindeberg, Staffan. Food and Western Disease: Health and Nutrition from an Evolutionary Perspective, Wiley-Blackwell, 2010." Auszug aus: Janine Schott. „Epigenetics explained." iBooks. https://itun.es/de/KxhUz.l) -research activity currently in progress -epigenetics may provide answers to fundamental question (e.g. Why is majority of population now over-fat?) (Book: Epigenetics explained) -defined as the interaction btw. genes and environment without an alteration of the DNA sequence - Epigenetics covers mechanisms which lead to regulatory processes of gene expression and maintain their degree of expression -furthermore includes investigation how condition is inherited in the course of cell divisions and finally how the interaction of epigenetic pattern and human genome works (Book: Epigenetics Territory and Cancer Source: Eggermann TB, Horsthemke B et al. (2013) Molekulargenetische Diagnostik von Imprintingerkrankungen. Med Genet 25:1-8) -course and intensity of gene activity are genetically determined but can be influences exogenously by different physical and chemical factors (e.g. inactivation of X-Chromosome) (Book: Epigenetics Territory and Cancer) -how each cell knows to turn on the right genes in genome to assume correct identity involves epigenetics -every gene regulated by promoter - epigenetics involves process of turning specific genes on or off in particular cells -most common way of controlling this gene expression is by plunking a molecule (methyl group) on the promoter region -where methyl groups end up and how many crowd a gene on genome determines whether gene is turned on or off (and if turned on how much it is expressed) http://time.com/3911161/explaining-epigenetics-the-health-buzzword-you-need-to-know/

Epigenetic profile

-collection of tags that tell gens whether to be on or off Cell's epigenetic profile is sum of signals received during lifetime (APA format: Genetic Science Learning Center (2014, June 22) The Epigenome learns from its experiences. Learn.Genetics. Retrieved December 27, 2015, from http://learn.genetics.utah.edu/content/epigenetics/epi_learns/ MLA format: Genetic Science Learning Center. "The Epigenome learns from its experiences." Learn.Genetics 27 December 2015 <http://learn.genetics.utah.edu/content/epigenetics/epi_learns/> Chicago format: Genetic Science Learning Center, "The Epigenome learns from its experiences," Learn.Genetics, 22 June 2014, <http://learn.genetics.utah.edu/content/epigenetics/epi_learns/> (27 December 2015)

Problems

-despite advancement in epigenetics knowledge, there are still many questions to be answered in epigenetics research (e.g. suitability of blood as a surrogate tissue to assess epigenetic changes and interpretation of genome wide DNA methylation information are questions to be answered) (Book: Environmental Epigenetics)

RNA Interference

-plays important role in controlling activity level of specific genes -exact roles and mechanisms still not fully explored (but rapidly expanding) -microRNA (miRNA)= type of small RNA molecule involved in RNA interference -miRNA= single stranded non-coding RNA, approx. 21-23 nucleotides in length -main function: down regulate gene expression by interfering with messenger RNA processes -miRNA suppresses gene expression by affecting miRNA stability, targeting miRNA for degradation, or both (Book: Environmental Epigenetics Source: Mathers JC, Strathdee G, Relton CL (2010) Induction of epigenetic alterations by dietary and other environmental factors. Adv Genet 71:3-39) -in limited cases miRNA may also increase gene transcription (Book: Environmental Epigenetics Source: Barros SP, Offenbacher S (2009) Epigenetics: connecting environment and genotype to phenotype and disease. J Dent Res 88(5):400-408) -about 1000 miRNAs have been identified in human cells (with potential to regulate expression of about 1/3 of human mRNAs and influence almost all genetic pathways through their effects on transcription factors, receptors, and transporters (Book: Environmental Epigenetics Source: Esquela-Kerscher A, Slack FJ (2006) Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer 6(4):259-269)

What controls epigenetic changes

-researchers still trying to find answer (leading candidates include exposure to things like tobacco and environmental pollutants) -diet may play role as well as things like stress http://time.com/3911161/explaining-epigenetics-the-health-buzzword-you-need-to-know/

Epigenetics and Inheritance

-some epigenetic tags remain in place as genetic information passes from generation to generation (process called epigenetic inheritance -little doubt that it is real) - goes against idea that inheritance happens only through DNA code that passes from parent to offspring -> parent's experience passed down to future generations Overcoming the Reprogramming barrier: -For reproduction, reproductive cells have to be reprogrammed in order to be able to form every type of cell in adult organism (reprogramming= epigenome is erased) -reprogramming very important as eggs and sperm develop from specialized cells with stable gene expression profiles (their genetic information is marked with epigenetic tags) -Yet small variety of genes don't return into "blank state"-> their epigenetic tags are passed unchanged to offspring APA format: Genetic Science Learning Center (2014, June 22) Epigenetics and Inheritance. Learn.Genetics. Retrieved December 27, 2015, from http://learn.genetics.utah.edu/content/epigenetics/inheritance/ MLA format: Genetic Science Learning Center. "Epigenetics and Inheritance." Learn.Genetics 27 December 2015 <http://learn.genetics.utah.edu/content/epigenetics/inheritance/> Chicago format: Genetic Science Learning Center, "Epigenetics and Inheritance," Learn.Genetics, 22 June 2014, <http://learn.genetics.utah.edu/content/epigenetics/inheritance/> (27 December 2015) -studies show that some epigenetic changes might be transmitted from one generation to the next -"It's still an open question to what extent that happens" (Azim Surani of the Wellcome Trust/Cancer Research Gurdon Institute at the University of Cambridge) -latest study, Surani and his colleagues studied how germ line cells are formed in an embryo -cells undergo type of epigenetic erasure (any metal groups added from mother's egg and father's sperm are removed -> growing fetus can create its own depending on its sex) -about 5% of methyl changes aren't wiped out (these genes predominantly involves in nerve and brain cell function as well as metabolic conditions-> could preferentially impact conditions like obesity/schizophrenia) (may explain how some epigenetic changes re-appear in offspring of parents (even if they aren't permanent alterations to genome but more like external modifications to how genes are regulated) http://time.com/3911161/explaining-epigenetics-the-health-buzzword-you-need-to-know/

Chromosome Instability

-stability of genome in general (chromosomes in particular) plays large role in several diseases (including cancer) -mechanisms by which stability is undetermined include DNA metabolism and repair gene silencing by aberrant methylation near CpG promoter regions, and accelerated telomere shortening -environmental+nutritional factors may control both mechanisms (e.g. zinc and magnesium levels help determine effectiveness of DNA repair and DNA metabolism (Book: Environmental Epigenetics Source: Bull C, Fenech M (2008) Genome-health nutrigenomics and nutrigenetics: nutritional requirements or 'nutriomes' for chromosomal stability and telomere maintenance at the individual level. Proc Nutr Soc 67(2):146-156)

Transposons

-transposable elements= sequences of DNA that move to new positions within genome of a single cell -Transposons among several types of transposable elements (plasmids,bacteriophages and certain introns) (Book. Environmental Epigenetics Source: Wicker T et al (2007) A unified classification system for eukaryotic transposable elements. Nat Rev Genet 8(12):973-982) -can behave as mutagens that cause genomic damage by various pathways -eukaryotic cells use RNA interference to silence transposable elements immediately after they are transcribed-> inhibits transposon activity levels to protect against genomic damage (Book: Environmental Epigenetics)

genetic assimilation

A process in which an environmentally induced phenotype, or "acquired characteristic," becomes genetically fixed such that the original stimulus that induced the phenotype is no longer required.

Epigenome learns from its experiences

Changing Epigenome Informs Gene Expression: -Epegenetic tags act as form of cellular memory as they record the cell's experiences on the DNA, helping to stabilize gene expression -each signal shuts down some genes and activates others -different experiences cause epigenetic profiles of each cell type to grow increasingly different over time (number of cell types form, each with distinct identity and specialized function) -In differentiated cell only 10-20% of genes are active (different sets of active genes make skin cell different from brain cell) Cells Listen for Signals: -epigenome changes in response to signals (can come from inside the cell, from neighboring cells or from outside world) Experiences Are Passed to daughter cells: -Epigenetic tags are copied during cell cycle (especially important during embryonic development as past experiences inform future choices) - epigenome allows cells to remember their past experiences long after signals fade away APA format: Genetic Science Learning Center (2014, June 22) The Epigenome learns from its experiences. Learn.Genetics. Retrieved December 27, 2015, from http://learn.genetics.utah.edu/content/epigenetics/epi_learns/ MLA format: Genetic Science Learning Center. "The Epigenome learns from its experiences." Learn.Genetics 27 December 2015 <http://learn.genetics.utah.edu/content/epigenetics/epi_learns/> Chicago format: Genetic Science Learning Center, "The Epigenome learns from its experiences," Learn.Genetics, 22 June 2014, <http://learn.genetics.utah.edu/content/epigenetics/epi_learns/> (27 December 2015)

Epigenetics in development of cells

Early in development: -most signals from within cell or from neighboring cells -Nutrition of mother also crucial role (food she brings into her body forms building blocks for shaping growing fetus and its developing epigenome) -signals like stress hormones can also travel from mom to fetus After birth and as life continues: -wider variety of environmental factors start to play role in shaping epigenome (social interactions, diet, physical activity...) -signals from within the body still important for many processes (e.g. physical growth) Old age: -cells continue to listen for signals -environmental signals cause changes in epigenome-> allows cell to respond dynamically to outside world -internal signals direct activities that are necessary for body maintenance

Epigenetic tags

Methylation of DNA or methylation/acetylation of histone proteins

non-coding RNA (ncRNA)

RNA molecules which are not transcribed whose functions to regulate gene expression at the transcriptional and post-transcriptional level. Epigenetic related ncRNAs include miRNA, siRNA, piRNA and lncRNA.

DNA methylation

The addition of a methyl (CH3) group from S-adenosylmethionine to a cytosine nucleotide or lysine or arginine residue. - inserting methyl groups changes appearance and structure of DNA -is used in some genes to differentiate which gene copy is inherited from the father and which gene copy is inherited from the mother(imprinting) http://www.nature.com/scitable/topicpage/epigenetic-influences-and-disease-895 -DNA methylation major epigenetic phenomenon that predominantly involves the covalent addition of a methyl group (CH3) to the 5'-position of cytosine that precedes a guanosine in the DNA sequence (the CpG dinucleotides)->regulates genetic expression and integrity in various biological processes (e.g. differentiation, genomic imprinting, DNA mutation, and DNA repair) (Book: Environmental Epigenetics Source: Fang M, Chen D, Yang CS (2007) Dietary polyphenols may affect DNA methylation. J Nutr 137 (1 Suppl):223S-228S) -referred to as epigenetic modification as it doesn't change coding sequence of DNA -it occurs on CpG sites (stretches of DG dinucleotides found in promotor regions) -Methyl-CpG binding proteins (MeCP1 and MeCP2) are actively recruited to methylated CpG sites (serve as base to recruit other protein to modify transcription) -> these proteins include DNA methyl transferase 1 (DNMT), histone methyl transferase(HMTs); and histone deacetylase (HDAC) -CpG dinucleotides not distributed evenly in whole genome (tend to be clustered in small stretches of DNA termed "CpG islands") (Book: Environmental Epigenetics Source: Robertson KD, Wolffe AP (2000) DNA methylation in health and disease. Nat Rev Genet 1(1): 11-19) -these regions often associated with promotor regions of genes -Approx. one-half of the genes in the human genome have such CpG-rich promoter regions (Book: Environmental Epigenetics Source: Herman JG, Baylin SB (2003) Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 349(21): 2042-2054) -majority of CpG dinucleotides not associated with CpG islands are heavily methylated (Book: Environmental Epigenetics Source: Herman JG, Baylin SB (2003) Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 349(21): 2042-2054) -on the contrary, dinucleotides in CpG islands usually are unmethylated (Book: Environmental Epigenetics Source: Bird A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16(1):6-21) -DNA methylation is an enzymatic process mediated by DNA methyltransferases -genomic methylation pattern is precisely inherited during mitosis and is highly tissue specific -Cytosine methylation changes structure of major groove in DNA molecule and disrupts attachment of DNA-binding proteins and transcription factors -genes methylated at specific sites are either not transcribed into messenger RNA or are transcribed at reduced rate -> reduces translation of gene into encoded protein -> Epigenetic DNA methylation contributes to control of gene and ultimately protein expression (Book: Environmental Epigenetics Source: Costello JF, Plass C (2001) Methylation matters. J Med Genet 38(5):285-303 also: Duthie SJ (2011) Epigenetic modifications and human pathologies: cancer and CVD. Proc Nutr Soc 70(1):47-56) -it can include the gene to turn on or off, and to up-or down-regulate) -for conservation of normal methylation pattern a sufficient function of DNA repair and methylation mechanisms necessary and of special relevance for cells with long life expectancy (with increasing age repair efficiency decreases- even methylation maintenance of specific genes can change-> can lead to altered gen regulation of the cell and the stability of the genome) (Book: Epigenetic territory and Cancer) -DNA methylation refers to the covalent addition of a methyl group to the C-5 atom of Cytosine (this methylation catalyzed by several DNA methyltransferases( establish methylation marks in development and maintain it during later cell divisions)) -Cytosine methylation predominantly occurs in CpG islands (CGIs) -these CpG-rich DNA sequences often found at transcription start site of genes (Book: Epigenetic Territory and Cancer Source: Bird A, Taggart M, Frommer M, Miller OJ, Macleod D (1985) A fraction of the mouse genome that is derived from islands of nonmethylated, CpG-rich DNA. Cell 40:91-99) -there they concede wit promoter regions of 70% of the human genes (Book: Epigenetic Territory and Cancer Source: Saxonov S, Berg P, Brutlag DL (2006) A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters. Proc Natl Acad Sci U S A 103:1412-1417) -methylation of CGIs imposes transcriptional silencing (transmitted by clonal inheritance in somatic cells) -general: methylation of promoter-related CGIs causes gene silencing - DNA methylation (in mammals) stably alters gene expression patterns in cells as basis for proper and orchestrated realization of genetic information during development and cell differentiation -also contributes to genome stability, parent-of-origin specific expression of imprinted genes and X-chromosome inactivation in female organisms -studying methylation status of CGIs in mammalian genome of major interest for deciphering the regulation mechanisms of gene expression (major challenge is that there is only one genome in one individual but hundreds of epigenomes as DNA methylation changes during development and is influenced by disease processes and environment) (Book: Epigenetic Territory and Cancer for review: Zhang TY, Hellstrom IC, Bagot RC, Wen X, Diorio J, Meaney MJ (2010) Maternal care and DNA methylation of a glutamic acid decarboxylase 1 promoter in rat hippocampus. J Neurosci 30:13130-13137)

Systems to silence genes

Within Cells there are 3 systems that can silence genes by interacting with each other: DNA methylation,histone modification, and RNA-associated silencing http://www.nature.com/scitable/topicpage/epigenetic-influences-and-disease-895

Nutrition and the Epigenome

nutrients extracted from food enter metabolic pathways where they are manipulated, modified, and modeled into molecules the body can use -> for example responsible for making methyl groups - important epigenetic tags that silences genes (e.g. folic acid, B vitamins key components for methyl- making pathway) -diet with too little methyl-donating folate or choline before or just after birth causes regions of genome to be under-methylated for life

History of Epigenetics

well-represented scientists including Conrad H. Waddington and Ernst Hadorn began broad research aiming to combine genetics and developmental biology during the mid 20th century-> developed into field of epigenetics -term epigenetic, coined by Waddington in 1942, was derived from Greek word "epigenesis" (originally described influence of genetic processes on development -during 1990s renewed interest in genetic assimilation -lead to elucidation of the molecular basis of Conrad Waddington's observations (environmental stress caused genetic assimilation of certain phenotypic characteristics in Drosophila fruit flies) - since then research efforts have been focused on unraveling the epigenetic mechanisms related to these types of changes -renewed interest has led to new findings about relationship betw. epigenetic changes and a host of disorders including various cancer, mental retardation associated disorders... - increased knowledge in epigenetics over least 10 years allow us to better understand interplay btw. epigenetic change, gene regulation, and human diseases, and will lead to development of new approaches for molecular diagnosis and targeted treatments across clinical spectrum (Sources http://www.whatisepigenetics.com/fundamentals/ used: 1.Egger G. et al. Epigenetics in human disease and prospects for epigenetic therapy. Nature 429, 457-463 (2004). Waddington C.H. "The epigenotype". Endeavour 1: 18-20 (1942) Brouwer J.R. (2012, April 4). A Crash Course in Epigenetics Part 1: An intro to epigenetics. Bitesize Bio. Retrieved June 18, 2013 from bitesizebio.com. Holliday, R. Epigenetics: A Historical Overview. Epigenetics, 1:2 76-80 (2006). -phenomenon of regulated gene expression already known for long time before term "Epigenetics" was introduced (Book: Epigenetic Territory and Cancer Source: Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A (2009) An operational definition of epigenetics. Genes Dev 23:781-783)