Epigenomics EpiGeromics

1. EpigenomicsEpiGeromics Jong Bhak

4. Epigenetic  Chromatin Structure • Most epigenetic research has converged on the study of covalent and noncovalent modifications of DNA and histone proteins as the mechanisms that directly influence chromatin structure. • https://www.youtube.com/watch?v=M4boKud1MRk

5. Chromatin structure Gene Expression • This is because the local chromatin environment of a given gene strongly influences its expression.

6. Definition: Epigenomics • is the study of the complete set of epigenetic modifications on the genetic material of a cell, known as the epigenome.

7. Reversible • Epigenetic modifications are reversible modifications on a cell’s DNA or histones that affect gene expression without altering the DNA sequence. • Modificaion affects Next generation • Cloning

8. Differentiation and Development & Tumorigenesis. • Epigenetic modifications play an important role in gene expression and regulation, and are involved in numerous cellular processes such as in differentiation and development and tumorigenesis.

9. EpiGeromics. • Epigenetic modifications play an important role in gene expression and regulation, and are involved in numerous cellular processes such as in differentiation and development and senescence.

10. Epigenomics Mechanisms RNA Interference Gene Expression DNA Methylation Histone Modifications DNA methylation, histone modifications, chromatin accessibility & small RNA transcripts

11. DNA Methylation Hypomethylation Hypermethylation http://www.cellscience.com/reviews7/Taylor1.jpg

12. DNA methyltransferase The DNA methyltransferase (DNA MTase) family of enzymes catalyze the transfer of a methyl group to DNA. DNA methylation serves a wide variety of biological functions. All the known DNA methyltransferases use S-adenosyl methionine (SAM) as the methyl donor.

13. DNA (cytosine-5)-methyltransferase 1 is an enzyme that in humans is encoded by the DNMT1 gene. Function DNA (cytosine-5-)-methyltransferase 1 has a role in the establishment and regulation of tissue-specific patterns of methylated cytosine residues. Aberrant methylation patterns are associated with certain human tumors and developmental abnormalities.

14. crystal structure of type i restriction enzyme ecoki m protein (ec 2.1.1.72) (m.ecoki)

15. S-Adenosyl methionine (SAM-e, SAMe, SAM, S-Adenosyl-L-methionine, AdoMet, ademetionine) is a common cosubstrate involved in methyl group transfers. SAM was first discovered in Italy by G. L. Cantoni in 1952

16. Natural Roles of DNA Methylation in Mammalian System • Imprinting • X chromosome inactivation • Heterochromatin maintenance • Developmental controls • Tissue specific expression controls

19. Heterochromatin

20. DNA Methylation and Cancer Robertson, Nature Reviews Genetics, Vol6, 597

21. DNA Methylation and Aging -- Imprinting Disorder: • Beckwith-Wiedemann syndrom (BWS) • Prader-Willi syndrome (PWS) • Transient neonatal diabetes mellitus (TNDM) -- Repeat-instability diseases • Fragile X syndrome (FRAXA) • Facioscapulohumeral muscular dystroph -- Defects of the methylation machinery • Systemic lupus erythemtosus (SLE) • Immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome

22. Histone Modifications http://porpax.bio.miami.edu/~cmallery/150/gene/c7.19.4.histone.mod.jpg

23. Histone Modifications http://www.nature.com/nsmb/journal/v14/n11/images/nsmb1337-F1.gif

24. Li e. al. (2007) Cell 128, 707

25. Histone Modifications in Relation to Gene Transcription Li e. al. (2007) Cell 128, 707

26. Histone Modifications and Human Diseases Coffin-Lowry syndrome is a rare genetic disorder characterized by and abnormalities of the head and mental retardation facial and other areas. It is caused by mutations in the RSK2 gene (histone phosphorylation) and is inherited as an X-linked dominant genetic trait. Males are usually more severely affected than females. Rubinstein-Taybi syndrome is characterized by short stature, moderate to severe intellectual disability, distinctive facial features, and broad thumbs and first toes.It is caused by mutations in CREB-binding protein (histone acetylation)

27. RNA Interference (RNAi) http://www.nature.com/ncpneuro/journal/v3/n7/images/ncpneuro0551-f1.jpg

28. siRNA Mediated Heterochromatin Maintenance

29. Technologies for Studying Epigenomics DNA Methylation Microarray or deep sequencing Irizarry et. Al. (2008) Genome Research 18(5):780

30. Biosulfite Treatment of Cytosine Treatment of DNA with bisulfite converts cytosine residues to uracil, but leaves 5-methylcytosine residues unaffected.

31. Bisulfite Sequencing

32. Bisulfite Sequencing

33. Non-methylation-specific PCR based methods

34. Knowing Difference? And Accepting Difference Importance of References

35. Genomic T 7 billion persons Genomic Diversity 6 billion Bases Genomic Variability Jong Bhak, under BioLicense

36. Geno+ Enviro=> Pheno (GEP/T graph) Pheno/Trait Geno Cancer Each Trait or Disease Flu Car accident Enviro  the atom of environment Jong Bhak. Under BioLicense: public domain.

37. (Making) Variation is the driving force of the universe Phene Variation Gene Variation Environe Variation Jong Bhak. Under BioLicense: public domain

38. Genome : Envirome :Phenome • Genome = gene types + their variome • Envirome= environe types + their variome • Phenome= phene types + their variome Jong Bhak. Under BioLicense: public domain

39. Prediction is what we doAll the algorithms in the world is to predict something Phenome • genome Uncertainty ? Envirome Jong Bhak. Under BioLicense: public domain

40. Complicated PheneComplexes • GeneComplexes EnviroComplexes Jong Bhak. Under BioLicense: public domain

41. Structure in Species Genomes Matrix 6 billion people billion Bases x 3(?) million animal species

42. Genomic T: Finding Structure in “Population” Matrix 6 billion people Billion Genome Project (BiG) http://billiongenome.com 7 billion Bases x 6 billion people

43. Geno-Enviro-Pheno TriPoint Comparative Genomic Sweet Spot Class Genus/Family, ….. Population Stratification Polymorphism Functional aberation Isolation (repro) Speciation, Functionally similar Distant homologs Functionally distinct

44. Aging and Cancer in a population Phenotypes by variations

45. The ultimate phenotype • Alive or Dead

46. Epigenetic Control of Aging • Ursula Muñoz-Najarand John M. Sedivy

47. Dynamic DNA/chromosome

48. Methylation pattern DNA methylation age of human tissues and cell types Steve Horvath

49. Histone and Protein modification