L’intestino nella prospettiva dell’epigenetica Domenico Mastrangelo

1. L’intestino nella prospettiva dell’epigenetica Domenico Mastrangelo Senior Scientist (research) Dipartimento di Scienze Mediche Chirurgiche e Neurologiche Università degli Studi di Siena

2. LA GENETICA MENDELIANA

4. GENE = porzione discreta di DNA che sintetizza una proteina Espressione genica = sintesi di una proteina da parte di un gene

5. REGOLAZIONE GENETICA DELL’ESPRESSIONE GENICA

7. HumanGenome Project (HGP) • 3,6 miliardi di paia di basi nel DNA genomico • costo dell’HGP – 2,7 miliardi dollari • numero di geni umani previsto > 100.000 • Drosophila 14.000 geni, pollo 23.000 geni; mais 59.000 geni; uomo 25.000 geni

8. Geni che codificano proteine Pseudogeni DNA non codificante Sequenze ripetitive DNA non codificante Sequenze uniche Spazzatura??? Spazzatura??? Spazzatura??? IL “MICROCOSMO” (DNA)

9. Atomi 6% Energia Oscura 23% Materia Oscura 73% IL “MACROCOSMO” (Universo)

10. 98% ofhumanchromosomes are “junk” DNA betweengenes. Largesections are remnantsof viral and bacterialinfections THE MYTH OF “JUNK” DNA … last fall, scientists with the international ENCODE (the Encyclopedia OfDNA Elements) consortium, launched by the National Genome Research Institute in 2003, announced what the authors said was a breakthrough in identifying all the functional elements in the human genome sequence. Published across 30 papers in Nature, the consortium claimed that long stretches of DNA, previously dismissed as “junk”, are in fact crucial to the way our genome works …

11. Collectively, the papers describe 1,640 data sets generated across 147 different cell types. Among the many important results there is one that stands out above them all: more than 80% of the human genome's components have now been assigned at least one biochemical function.

12. LA GENETICA MENDELIANA NON SPIEGA … … come si possa generare tanta diversità fenotipica e complessità funzionale a partire da uno stesso (ed unico) DNA! …

13. MUTAZIONI alterazioni della struttura del DNA … … o dei cromosomi di cui il DNA rappresenta l’ossatura …

14. EPIGENETICA … il termine fu coniato nel 1942 da Conrad HalWaddington, per definire: “ … lo studio delle modificazioni ereditabili dell’ espressione genica o del fenotipo cellulare, non legate a cambiamenti della struttura del DNA.”

15. MECCANISMI DI REGOLAZIONE EPIGENETICA DELL’ESPRESSIONE GENICA

16. MECCANISMI DI REGOLAZIONE EPIGENETICA DELL’ESPRESSIONE GENICA

17. MECCANISMI DI REGOLAZIONE EPIGENETICA DELL’ESPRESSIONE GENICA

18. MECCANISMI DI REGOLAZIONE EPIGENETICA DELL’ESPRESSIONE GENICA

21. Una sola cellula… un solo DNA e … migliaia di fenotipi cellulari … Il DNA delle cellule germinali presenta numerosi “tags” epigenetici in quanto tutte le cellule di un individuo adulto sono “specializzate” per svolgere compiti definiti. Con la fecondazione questi “tags” vengono rimossi e l’oocita può trasformarsi in qualsiasi tipo di cellula …

22. L’EPIGENETICA (non la genetica mendeliana!) SPIEGA … … come si possa generare tanta diversità fenotipica e complessità funzionale a partire da una singola cellula! …

23. EPIGENETICA • Principi: • L’espressione genica non dipende (solo) da cambiamenti (mutazioni) nella struttura del DNA • Il “fenotipo” cellulare” (l’aspetto e le caratteristiche di una cellula) non è dovuto (solo) a cambiamenti (mutazioni) della struttura del DNA • Un “fenotipo” cellulare può essere ereditato indipendentemente da cambiamenti (mutazioni) nella struttura del DNA

25. Epigenetics, or why the question isn't "Environment OR Genetics"

26. ENVIRONMENT = The combination of external physical conditions that affect and influence the growth, development, and survival of organisms

27. … environmental factors may exert neurobiological and behavioral effects through epigenetic changes. “Environment” in this context can be used in the very broad sense and include hormonal, social, nutritional, and toxicological exposures occurring prenatally, postnatally, or in adulthood. During prenatal development, adverse experiences are associated with a heightened risk of physical and psychiatric dysfunction … (Champagne FA, Risman EF: Behavioral epigenetics: A new frontier in the study of hormones and behavior. Hormones and Behavior 59 (2011) 277–278) Beta-adrenergic signaling from the sympathetic nervous system has been found to up-regulated a diverse array of genes that contribute to tumor progression and metastasis, whereas glucocorticoid-regulated genes can inhibit DNA repair and promote cancer cell survival and resistance to chemotherapy… (Cole SW: Nervous system regulation of the cancer genome. Brain, Behavior, and Immunity 30 (2013) S10–S18)

28. Jean-Baptiste Lamarck (1744-1829) is best remembered for a discredited theory of heredity, the "inheritance of acquired traits." He proposed that environment changes caused changes in behavior which in turn led to the increase or decrease of particular structures. Lamarck had a colorful and distinguished career: in turns soldier, bank clerk, Professor of "insects and worms" he died a poor man and was buried in a rented grave.

29. It is increasingly recognized that environmental exposure to chemical, nutritional and behavioral factors alters gene expression and affects health and disease by not only mutating promoter and coding regions of genes, but also by modifying the epigenome. Faulk C, Dolinoy DC: Timing is everything: The when and how of environmentally induced changes in the epigenome of animals Epigenetics 6:7, 791-797; July 2011;

30. CANCER EPIGENETICS

35. L’ereditarietà dei caratteri acquisiti … J.B.Lamarck

37. ?

38. a) Dietary supplementation of female mice during pregnancy. The diets of female a/a mice are supplemented with methyl-donating substances (that is, folic acid, choline, vitamin B12 and betaine) or the phytoestrogen genistein 2 weeks before mating with male Avy/a agouti mice, and throughout pregnancy and lactation ? b) Maternal dietary supplementation and coat-colour distribution in Avy/a offspring. The coat colour is primarily yellow in the offspring that are born to unsupplemented mothers, whereas it is mainly brown in the offspring from mothers that were supplemented with methyl-donating compounds or genistein. 

41. L’intestino è la sede principale del sistema immunitario …

43. L’epigenetica e’ alla base del funzionamento del sistema immunitario During the differentiation of T and B cells, immune-receptor loci in the genome must be made sterically accessible so that they can undergo rearrangement. Here, we discuss how this is carried out by the stepwise removal of epigenetic repression mechanisms — such as later-replication timing, heterochromatization, histone hypo-acetylation and DNA methylation — in a manner that initially favours one allele in each cell. We propose that this mechanism of allelic exclusion might also be the basis for the generation of gene diversity in other systems.

44. L’epigenetica e’ alla base del funzionamento del sistema immunitario

45. L’epigenetica e’ alla base del funzionamento del sistema immunitario

46. L’epigenetica e’ alla base del funzionamento del sistema immunitario

48. THE HUMAN MICROBIOME

49. The human microbiome refers to all of the microbial organisms that reside in the body including bacteria, fungi, and archaea.  Notably, the human body contains over 10 times more microbial cells than human cells!

50. … il rapporto cellule/batteri, nell’organismo normale, è 1/10 (per ogni cellula, 10 batteri! …)