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Epigenetics Heritable alterations in chromatin structure can govern gene

Epigenetics Heritable alterations in chromatin structure can govern gene expression without altering the DNA sequence. Viterbo Università degli Studi della Tuscia. Epigenetics denotes all those hereditary phenomena in which the phenotype is not only

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Epigenetics Heritable alterations in chromatin structure can govern gene

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  1. Epigenetics Heritable alterations in chromatin structure can govern gene expression without altering the DNA sequence. Viterbo Università degli Studi della Tuscia

  2. Epigenetics denotes all those hereditary phenomena in which the phenotype is not only determined by the genotype (the DNA sequence itself) but also by the establishment over the genotype (in greek “epi” means “over”) of an imprint that modulates its functional behavior

  3. Vertebrates, Invertebrates and Plants Genic, chromosome and genomic imprinting Heterochromatin formation Eukaryotes Eukaryotes Centromere function Mammals Polycomb group proteins Drosophila RNA interference (PTGS) Transvection Drosophila Paramutation Plants RIP e MIP (Quelling) Fungi Epigenetic phenomena

  4. Genic, chromosome or genomic IMPRINTING

  5. x A Sciara coprofila maternal genome paternal genome x A x zygote x x x embryo embryo A x x A A x A Differential behavior of homologous chromosomes The chromosome which passes through the male germ line aquires an imprint that results in behaviour exactly opposite to the imprint conferred on the same chromosome by the female germ line (H. Crouse, 1960)

  6. M P zygote M P P M P M P M Nuclear transplantation in mammals androgenetic embryos (two male pronuclei) gynogenetic embryos (two female pronuclei) Poor development of the embryo proper Poor development of extraembryonic components

  7. Angelman, Prader-Willi syndromes • Usually caused by large (megabase+) deletions of 15q11-q13 • Delete maternal chromosome = AS • Delete paternal chromosome = PWS

  8. Prader-Willi Syndrome - obesity, mental retardation, • short stature. • Angelman Syndrome - uncontrollable laughter, jerky • movements, and other motor and • mental symptoms.

  9. PWS Mouse model PWS AS Mouse model AS

  10. Imprinting cycleestablishment, maintenance and erasure

  11. What Mendel (fortunately) didn’t find in his experiments with peas 1:1

  12. NO Does the genomic imprinting falsifies the Mendel’s rules? Neither the segregation of single gene alleles, nor the indipendent behavior of different genes are affected by the existence of imprinting What the imprinting may mask are the dominance relations between alleles, and hence only the phenotypic output of a cross

  13. HETEROCHROMATIN NUCLEATION AND MAINTENANCE

  14. In 1928, Heitz defined the heterochromatin as regions of chromosomes that do not undergo cyclical changes in condensation during cell cycle as the other chromosome regions (euchromatin) do. • Heterochromatin is not only allocyclic but also very poor of active genes, leading to define it as genetically inert (junk DNA). • Heterochromatin can be subdivided into two classes: constitutive heterochromatin and facultative heterochromatin. • Constitutive heterochromatin indicates those chromatin regions that are permanently heterochromatic. These regions occupy fixed sites on the chromosomes of a given species, are present in both homologous chromosomes, throughout the life cycle of the individual. • Facultative heterochromatization is a phenomenon leading to the developmentally or tissue-specific co-ordinate reversible inactivation of discrete chromosome regions, entire chromosomes or whole haploid chromosome sets.

  15. Drosophila melanogaster X chromosome W+ pericentric heterochromatin White+ W- inversion W+ Y White+ Wm4 Wm4 W- Wm4 Y Position Effect Variegation (PEV)

  16. In all cases an inversion or translocation changed the position of the gene from a euchromatic to heterochromatic position this results in variegation • Some rearrangements gave large patches of red facets adjacent to large patches of white Conclusion: Decision on expression of white is made early during tissue development and maintained through multiple cell divisions • Gene is not mutated – movement of the rearranged allele away from heterochromatin can restore expression • PEV is not limited to Drosophila: see telomeric silencing in yeast

  17. X chromosome inactivation The Barr body XY XX XXX XXXXX XXXXY

  18. Genotype is Xyellow/Xblack Yellow patches: black allele is inactive Black patches: yellow allele is inactive Xyellow/Xblack Xyellow/Xblack In mammals the dosage compensation of the X chromosome products, between XX females and XY males is achieved by inactivating one of the two Xs in each cell of a female (Mary Lyon, 1961)

  19. Coccid chromosome system paternal chromosomes maternal chromosomes zygote embryo embryo Planococcus citri (2n=10) imprinted facultative heterochromatization

  20. Female and male cells from P.citri

  21. PARAMUTATION Alexander Brink x B-I B’ x B’/B-I* B-I B’/B-I B-I*/B-I

  22. MOLECULAR MECHANISMS OF EPIGENETICS

  23. The chromatin

  24. nucleosomes Histone protein modifications DNA histones DNA modifications

  25. HISTONE PROTEIN MODIFICATIONS

  26. …9KMe …4KMe …20KMe …16KAc chromatin 20KMe 9KMe 9KMe 20KMe 16KAc 4KMe 4KMe 16KAc 16KAc 16KAc 4KMe 9KMe 9KMe 20KMe euchromatin heterochromatin Acetylation Phosforylation Methylation Ubiquitination H3 H4 H2A H2B

  27. chromatin non histone chromatin proteins: HP1 9KMe 9KMe 9KMe euchromatin heterochromatin HP1 and modified histone tails interactions during heterochromatin formation

  28. Histone Code and Transcriptional Silencing Epigenetic modifications leading to gene silencing. (A) Gene repression through histone methylation. Histone deacetylase deacetylates lysine 9 in H3, which can then be methylated by HMTs. Methylated lysine 9 in H3 is recognised by HP1, resulting in maintenance of gene silencing. B) Gene repression involving DNA methylation. DNA methyltransferases methylate DNA by converting SAM to SAH, a mechanism that can be inhibited by DNMT inhibitors (DNMTi). MBPs recognise methylated DNA and recruit HDACs, which deacetylate lysines in the histone tails, leading to a repressive state. (C) Interplay between DNMTs and HMTs results in methylation of DNA and lysine 9 in H3, and consequent local heterochromatin formation. The exact mechanism of this cooperation is still poorly understood.

  29. Histone Code and Transcriptional Activation Epigenetic modifications leading to gene activation. (A) Setting 'ON' marks in histone H3 to activate gene transcription. Lysine 4 in H3 is methylated by HMT (for example MLL) and lysine 9 is acetylated by HAT, allowing genes to be transcribed. It is not known, if HMTs and HATs have a direct connection to each other. (B) In the postulated 'switch' hypothesis, phosphorylation of serines or threonines adjacent to lysines displaces histone methyl-binding proteins, accomplishing a binding platform for other proteins with different enzymatic activities. For example, phosphorylation of serine 10 in H3 may prevent HP1 from binding to the methyl mark on lysine 9. Other lysines in H3 may be acetylated by HATs, therefore overwriting the repressive lysine 9 methyl mark and allowing activation. (C) Although there is no HDM identified to date, one can speculate that, if this enzyme exists, serine 10 phosphorylation in H3, for example, by Aurora kinases, can lead to recruitment of HDMs that in turn demethylate lysine 9 in H3. Histone acetyltransferases might then acetylate lysine 9 and HMTs methylate lysine 4, resulting in the loosening of the chromatin structure and allowing gene transcription.

  30. Histone Modification Cassettes Methylation of Lys-9 by DIM-5 (SUVAR39H1) recruits HP1 via its chromodomain. In turn, HP1 can recruit additional SUVAR39H1 and other silencing proteins to establish heterochromatin. Phosphorylation of Ser-10 abolishes methylation of Lys9 by DIM-5 (SUVAR39H1) and binding of the HP1, thereby blocking heterochromatin formation. Phosphorylation of Ser-10 can modestly stimulate acetylation of Lys14 by GCN5, thus promoting transcription. Lys-9 and Ser-10 have been referred to as a methyl/phos switch: Fischle W, Wang Y, Allis CD. Nature. 2003;425:475-9.

  31. DNA MODIFICATIONS

  32. Imprinting cycle/DNA metylation cycleestablishment, maintenance and erasure m m m m m m maintenance embryonic divisions maintenance methylase m m somatic cells reversion de novo establishment gametogenesis demethylase de novo methylase m m m m gametes Maternal genome Paternal genome zygote

  33. Heterochromatin, HP1 and histone tail modifications dapi HP1 Histone H4 lysine 20 methylation dapi HP1 m9KH3 merge merge m9KH3 Histone H3 lysine 9 methylation

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