Epigenetic Was Lamarck still right? Was Lamarck still right?
Epigenetic Was Lamarck still right? Epigenetik/ v. Eggeling 1 1. Introducing Epigenetics 2. Molecular basis 3. Imprinting 4. Diseases as a model for Epigenetics 5. Methylation and demethylation in development 6. Epigenetic phenomena during cloning and at artificial fertilization 7. Heritage of environment or acquired traits - or was Lamarck still right? Epigenetik/ v. Eggeling 2 1 Introducing Epigenetics Epigenetik/ v. Eggeling 3 Definition Epigenetik: (επι [gr]: beneath, over) In biology, the term epigenetics refers to changes in phenotype (appearance) or gene expression caused by mechanisms other than changes in the underlying DNA sequence, hence the name epi- (Greek: over; above) genetics. These changes may remain through cell devision for the remainder of the cell's life and may also last for multiple generations. However, there is no change in the underlying DNA sequence of the organism; instead, nongenetic factors cause the organism's genes to behave (or "express themselves") differently. Die Epigenetik betrifft Vorgänge, die sich ‘epi’ - d. h. neben oder über der DNA abspielen und dazu führen, daß die kodierte Information in einem Gen aktiv wird und einen bestimmten zellulären Prozeß in Gang setzt, der schließlich zur Ausprägung eines bestimmten Merkmals (Phänotyps) des Individuums führt Epigenetik/ v. Eggeling 4 Epigenetic How epigenetic phenomena were found? Nucleus transplantation experiments with mice Egg with only female nuclei ? Small placenta Abortion of fetuses Egg with only male nuclei ? Big placenta Epigenetik/ v. Eggeling 5 Epigenetic ..but also 3000 years ago epigenetic phenomena were visible in breeding .... Maultier (Kreuzung von Eselhengst [donkey] und Pferdestute [mare]): mule Maulesel (Kreuzung von Pferdehengst [stallion] und Eselstute): hinny Epigenetik/ v. Eggeling 6 Conclusion • These results are not compatible with Mendels rules • There must be factors that lead to differences depending whether the DNA is processed over oogenesis or spermatogenesis Epigenetik/ v. Eggeling 7 Gliederung 2 Molecular bases Epigenetik/ v. Eggeling 8 Nukleosomen Nukleosomen bei der Verpackung von DNA Den Kern der Nukleosomen bilden die Histone H2A, H2B, H3, H4 (je 2x) Epigenetik/ v. Eggeling 9 Molecular bases of Epigenetics • Methylation of so-called CpG-Island Here one methyl group (CH3) is added to the cytosine • Histon deacethylation • Methylation and histon deacetylation suppress transcription • Inactivation by methylation is known for Fungi Plants Mammals Epigenetik/ v. Eggeling 10 Molecular bases of Epigenetics (active) (inactive) Interaction with heterochromatin proteins H3K9 acetylation H3K4 metylation DNA Methylation H3K27 methylation Euchromatin proteins Epigenetik/ v. Eggeling 11 The cellular memory or the histon code Nucleosomes with modified tails are carrier of epigenetic information. Especially important for the inheritance of gene expression Azetyliertes Lysin Ubiquiniertes Lysin Methyliertes Lysin Phosphoryl-Lysin Methyliertes Arginin Epigenetik/ v. Eggeling 12 Changing chromatin structure • The histon code allow a high number of modification • 50 Million CpG sites could be methylated or un-methylated in a haploid genome • 25000000 combinatorial options for the methylation pattern • For this reason the epigenetic variety could very high Epigenetik/ v. Eggeling 13 The cellular memory or the histon code Epigenetik/ v. Eggeling 14 3 Imprinting Epigenetik/ v. Eggeling 15 Imprinting Definition: [imprint (engl.): aufdrücken, einprägen] Genomic imprinting is a genetic phenomenon by which certain genes are expressed in a parent-of-origin-specific manner. It is an inheritance process independent of the classical Mendeleian inheritance. Imprinted genes are either expressed only from the allele inherited from the mother (eg. H19 or CDKN1C), or in other instances from the allele inherited from the father (eg. IGF2). Forms of genomic imprinting have been demonstrated in insects, mammals and flowering plants. Genomic imprinting is an epigenetic process that involves methylation and histone modifications in order to achieve monoallelic gene expression without altering the genetic sequence. These epigenetic marks are established in the germline and are maintained throughout all somatic cells of an organism. Beim Imprinting wird festgelegt, welche Gene von der Mutter oder dem Vater für eine normale Entwicklung des Kindes ab- bzw. angeschaltet werden müssen Epigenetik/ v. Eggeling 16 Imprinting • Zygotes with only maternal or only paternal genetic material result not in normal offspring • Male and female provide an not equal genetic contribution to offspring • In men 100 – 200 genes were assumed to be affected by imprinting (e. g. sex-specific differentially methylated) Epigenetik/ v. Eggeling 17 Imprinting GEN A Mat. Allel Pat. Allel GEN B Mat. Allel Pat. Allel Epigenetik/ v. Eggeling 18 Gliederung 4 Diseases as a model for epigenetic Epigenetik/ v. Eggeling 19 Imprinted chromosomal regions Epigenetik/ v. Eggeling 20 Diseases as a model for epigenetic • Uniparental Disomies • Mutations in the methylation machinery • Hypo- or hyper methylation in carcinogenesis Epigenetik/ v. Eggeling 21 Uniparental Disomies (UPD) Here there is no false imprinting, but the chromosomes of one single parent are passed to the offspring. Microsatellite analysis But the effect is the same Zygote pat mat Normal mat mat UPD Epigenetik/ v. Eggeling 22 Imprinted chromosomal regions Epigenetik/ v. Eggeling 23 Uniparentale Disomies (UPD) Angelman-Syndrom (AS) and Prader-Willi-Syndrom (PWS) [15q11-13] normal situation PWS AS mat pat Angelman Syndrome PWS Prader-Willi syndrome AS uniparental Disomy PWS AS pat mat pat mat active Gene inactive Gene Epigenetik/ v. Eggeling 24 Mutations in the methylation machinery DNA-Cytosin-Methyltransferases DNMT1 DNMT3a DNMT3b Methylation of hemimethylated DNA new methylation new methylation Methyl-CpG-binding proteins MECP2 Mediate between methylation and deazetylation Epigenetik/ v. Eggeling 25 Mutations in the methylation machinery DNMT1 ATR-X Syndrom (-thalassaemia, mental retardation, X-linked) DNMT3 FMR1 ICF Syndrom (Immune-deficience, centromeric instability, facial anomaly) Fra X Syndrom (fragile X) MeCP2 RETT Syndrom Epigenetik/ v. Eggeling 26 Mutations in the methylation machinery Rett syndrome – Defect Methyl binding protein Binding to methyl groups leads to a deacetylation of local histones and thereby to suppression of transcription The Rett syndrome is the most common cause of mental retardation in women (lethal for male embryos; ca. 1:10000) Epigenetik/ v. Eggeling 27 Rett syndrome DNA Methylation H3K9 acetylation H3K4 metylation H3K27 methylation Interaction with heterochromatin proteins Euchromatin proteins Epigenetik/ v. Eggeling 28 Beckwith-Wiedemann Syndrom (BWS) maternal paternal active inactive chromatin disruption Epigenetik/ v. Eggeling 29 Cancer and methylation Inactivation of the tumor suppressor gene p16 by methylation Promotor exon 1 CpG islands exon 2 exon 3 RNA Tumor suppressor (Protein) M M M M M M exon 1 exon 2 exon 3 no suppressor Further proliferation of maligne cells Epigenetik/ v. Eggeling 30 Epigenetik/ v. Eggeling 31 Cancer and methylation • Global hypo-methylation, but local hyper-methylation • Silencing of TSGs leads to growth advantage (methylation of pRB leads to unilateral Retinoblastoma, of VHL renal cell carcinoma) • Silencing of mismatch repair genes (MMR) stops repair -> accumulation of mutation • Elevated methylation with age • 5-Methylcytosine could chemically affected easily -> mutations (e.g. Melanoma: meth-C -> UV -> T) Epigenetik/ v. Eggeling 32 Methylation and aging Epigenetik/ v. Eggeling 33 Summary (Imprinting and diseases) • For the proper development of offspring the appropriate genes has to be imprinted • So, for one gene the maternal allele has to be inactivated, but the paternal activated. For another gene it could be vice versa • False imprinting pattern, but also defects or loss of enzymes, which act methylation, result in several diseases Epigenetik/ v. Eggeling 34 Gliederung 5 Methylation und Demethylation during Development Epigenetik/ v. Eggeling 35 Methylation und Demethylation during Development Epigenetik/ v. Eggeling 36 Methylation und Demethylation during Development Generationswechsel imprinted methylated genes imprintete non-methylated genes non-imprinted maternal genes non-imprinted paternal genes Epigenetik/ v. Eggeling 37 Detection of Methylation Immuno staining of a mouse zygote with Anti-5-Methylcytosin paternal 3h 6h 8h maternal 2 cell-state 22h 32h 4 cell-state 45h Meyer et al. 2000 Epigenetik/ v. Eggeling 38 Where epigenetic modifications can be set? Deletion of methylation of not imprinted genes Fertilization Embryo Environmental impacts Adult Germ cells Deletion of all methylation Cloning and in-vitro Fertilization (IVF) can lead to problems! Epigenetik/ v. Eggeling 39 Epigenetik/ v. Eggeling 40 Summary (Methylation and Development) • Methylation or imprints will be deleted in primordial germ cells and in zygote completely or partially, respectively • How acquired characteristics or influences from development can be inherited? Epigenetik/ v. Eggeling 41 6 Epigenetic phenomena during cloning and invitro fertilization Epigenetik/ v. Eggeling 42 Epigenetic und Cloning Somatic cell Enucleated egg Genome of only one single parent! Clone Epigenetik/ v. Eggeling 43 Epigenetic und Cloning The cloned lamb is bigger and dies earlier! Epigenetik/ v. Eggeling 44 Epigenetic und in-vitro fertilization (IVF) Also by in-vitro fertilization and especially by ICSI (intra cytoplasmatic Sperm injection) there are data indicating on problems: Children are smaller The probability by ICSI is higher for BeckwithWiedemann Syndrome (11p15) Children get more often a Retinoblastom Epigenetik/ v. Eggeling 45 7 Heritage of environmental influences or acquired traits - was Lamarck still right? Epigenetik/ v. Eggeling 46 Heritage of environmental influences or acquired traits Drosophila (fruit fly) Special elements (Fab-7) can be inherited epigenetically through mitosis and meiosis (Cavalli und Paro 1998; Cell) Epigenetik/ v. Eggeling 47 Heritage of environmental influences or acquired traits Mouse: Special nutrition Fur color stays changed over generations Treatment with cancerogenic drugs Also offspring have a higher incidence for tumors Malnutrition Offspring are smaller Epigenetik/ v. Eggeling 48 Heritage of environmental influences or acquired traits Human: Father have had a low intake in his SGP Lower lethality from cardiovascular diseases Generally reach higher age Grandfather has eaten a lot Macrodome of mother by malnutrition during early embryonic development High lethality from diabetes Children with lower weight and height Epigenetik/ v. Eggeling 49 Darwin und Mendel Darwin postulated selection as main mechanism in evolution Charles Darwin (1809-1882) Mendel proved that traits can be inherited in a special way Gregor Mendel (1822-1884) Epigenetik/ v. Eggeling 50 Was war Lamarcks Theorie? Quintessence of Lamarckism Animal adapt to a changing environment. The acquired traits are inherited, if both parents possess them Jean-Baptiste Lamarck (1744-1829) • Introduced the term „Biology“ • Introduced the term of animal classes Epigenetik/ v. Eggeling 51 Lamarcks therory as als ideology Trofim Lyssenko (1898-1976) -> Lyssenkoism • Aquired traits could be inherited • Species can be convertedt o each other He is responsible for the shameful backwardness of Soviet biology and of genetics in particular, for the dissemination of pseudoscientific views, for adventurism, for the degradation of learning, and for the defamation, firing, arrest, even death, of many genuine scientists (1964). Epigenetik/ v. Eggeling 52 Georg Schneider (1909-1970) Director of the Ernst-Haeckel-House. Brought theories of Lyssenkos to Jena Epigenetik/ v. Eggeling 53 Bisherige Kritik an Lamarcks Theorie Criticism to Lamarck's evolution theory: Lamarcks evolution theory has a big error, because it tells that individually aquired traits will be inherited; that means that genetic information has to be changed in the germ cells. Epigenetik/ v. Eggeling 54 Epigenetik/ v. Eggeling 55 Facts to caesarean section; •In Brasilia 4 of 5 women •In USA 4 of 10 •In Germany 3 of 10 Allergy Astma Diabetes Typ 1 20 % higher methylation of lymphocytes Is birth may be to fast? Epigenetik/ v. Eggeling 56 Fearless by methylation antagonists? • Suizid patients – special genes in brain are higher methylated • Children misused have lower activity of glucocortikoid receptor • Rats with deficits in parental care have a lower stress tolerance Epigenetik/ v. Eggeling 57 Some additional Facts: Epigenetik/ v. Eggeling 58 70% of the human genome are transcribed - but only 2% encode for proteins! | © dkfz.de Epigenetik/ v. Eggeling 59 Short and long noncoding RNA Coding or functional RNA (fRNA) Noncoding RNA (ncRNA) Small nucleolar (snoRNA) Transfer RNA (tRNA) Ribosomale RNA (rRNA) microRNA (miRNA) Short/small interferring (siRNA) Long noncoding (lncRNA) Piwiinteracting (piRNA) Piwi: P-element induced wimpy testis (Drosophila) Epigenetik/ v. Eggeling 60 Long non-coding RNAs (long ncRNAs, lncRNA) are in general considered (somewhat arbitrarily) as non-protein coding transcripts longer than 200 nucleotides. A recent study found only one-fifth of transcription across the human genome is associated with protein-coding genes, indicating at least four-times more long non-coding than coding RNA sequences. But lncRNA could also code for proteins! Epigenetik/ v. Eggeling 61 Epigenetik/ v. Eggeling 62 Epigenetik/ v. Eggeling 63 2011 Epigenetik/ v. Eggeling 64 Conclusion: • Epigenetic is an additional way of inheritance • Investigation in men and mice could show that influences of environment can be transmitted to the next generation • The molecular mechanisms stay unclear until now • The evolutionary advantage of epigenetic could be a faster adaption to a changing environment Epigenetik/ v. Eggeling 65 What is coming up? Epigenetik/ v. Eggeling 66 Zusätzliche Folien Epigenetik/ v. Eggeling 67 Hatte jetzt Lamarck doch recht? JA und NEIN Epigenetik ist ein zusätzliche Form der Vererbung Umwelteinflüsse können über Generationen weitergegeben werden. Können dies aber erworbene Eigenschaften sein? Molekulare Mechnismen, die eine epigenetische Vererbung über Generationen ermöglichen sind bisher nur ansatzweise erkannt Epigenetik/ v. Eggeling 68 Durch wissenschaftliche Forschungen hat das anthropozentrische Weltbild viele Kränkungen erfahren Kopernikus Darwin Human Genom Projekt Epigenetik/ v. Eggeling 69 Epigenetik/ v. Eggeling 70 Epigenetik/ v. Eggeling 71 Epigenetik/ v. Eggeling 72 Epigenetik/ v. Eggeling 73 Epigenetik/ v. Eggeling 74 Epigenetik/ v. Eggeling 75 Epigenetik/ v. Eggeling 76 Epigenetik/ v. Eggeling 77 Methylierung und Demethylierung Epigenetik/ v. Eggeling 78 Molekulare Grundlagen der Epigenetik Methylierung Nachteile • Erhöhung der Mutationsrate (5-Methylcytosine als endogenes Mutagen) • Wichtige Gene, die die Proliferation steuern, können inaktiviert werden (z. B. TSG, MMR) • Änderung der Stabilität der Chromatinstruktur • Homologe Rekombination ist reduziert Vorteile • X-Chromosome Inaktivierung • Suppression von parasitären Sequenzen • Imprinting Epigenetik/ v. Eggeling 79 Begriffsdefinition Genetik Epigenetik wie können Umwelteinflüsse zu Mutationen in den Genen führen? Können Umwelteinflüsse den regulatorischen Zustand der Gene verändern? Epigenetik/ v. Eggeling 80 Molecular bases of Epigenetics common disease genetic and epigenetic (CDGE) Epigenetik/ v. Eggeling 81 Jean Baptiste Lamarck Rudyard Kipling „adaptive change“ Epigenetik/ v. Eggeling 82
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