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Doug Brutlag 2011 Genomics, Bioinformatics & Medicine Doug Brutlag Professor Emeritus of.

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Presentation on theme: "Doug Brutlag 2011 Genomics, Bioinformatics & Medicine Doug Brutlag Professor Emeritus of."— Presentation transcript:

1 Doug Brutlag 2011 Genomics, Bioinformatics & Medicine Doug Brutlag Professor Emeritus of Biochemistry & Medicine Stanford University School of Medicine Epigenetics

2 Doug Brutlag 2011 What is Epigenetics? C.H. Waddington coined the term epigenetics to mean above or in addition to genetics to explain differentiation. How do different adult stem cells know their fate? o Myoblasts can only form muscle cells o Keratinocytes only form skin cells o Hematopoetic cells only become blood cells o But all have identical DNA sequences.

3 Doug Brutlag 2011 C.H. Waddington

4 Doug Brutlag 2011 What is Epigenetics? C.H. Waddington coined the term epigenetics to mean above or in addition to genetics to explain differentiation. How do different adult stem cells know their fate? o Myoblasts can only form muscle cells o Keratinocytes only form skin cells o Hematopoetic cells only become blood cells o But all have identical DNA sequences. Modern definition is non-sequence dependent inheritance. How can identical twins have different natural hair colors?

5 Doug Brutlag 2011 Identical Twins with Different Hair Color

6 Doug Brutlag 2011 What is Epigenetics? C.H. Waddington coined the term epigenetics to mean above or in addition to genetics to explain differentiation. How do different adult stem cells know their fate? o Myoblasts can only form muscle cells o Keratinocytes only form skin cells o Hematopoetic cells only become blood cells o But all have identical DNA sequences. Modern definition is non-sequence dependent inheritance. How can identical twins have different natural hair colors? How can a single individual have two different eye colors?

7 Doug Brutlag 2011 Mosaicism: An Individual with Two Different Eye Colors “Diego”

8 Doug Brutlag 2011 Mosaicism: An Individual Eye with Two Colors

9 Doug Brutlag 2011 What is Epigenetics? C.H. Waddington coined the term epigenetics to mean above or in addition to genetics to explain differentiation. How do different adult stem cells know their fate? o Myoblasts can only form muscle cells o Keratinocytes only form skin cells o Hematopoetic cells only become blood cells o But all have identical DNA sequences Modern definition is non-sequence dependent inheritance. How can identical twins have different natural hair colors? How can a single individual have two different eye colors? How can identical twin liter mates show different coat colors?

10 Doug Brutlag 2011 Coat Colors of Genetically Identical Agouti Mice Liter Mates

11 Doug Brutlag 2011 What is Epigenetics? C.H. Waddington coined the term epigenetics to mean above or in addition to genetics to explain differentiation. How do different adult stem cells know their fate? o Myoblasts can only form muscle cells o Keratinocytes only form skin cells o Hematopoetic cells only become blood cells o But all have identical DNA sequences. Modern definition is non-sequence dependent inheritance. How can identical twins have different natural hair colors? How can a single individual have two different eye colors? How can identical twin liter mates show different coat colors? How can just paternal or maternal traits be expressed in offspring? This is called genetic imprinting. How can females express only one X chromosome per cell? How can acquired traits be passed on to offspring? Some changes in gene expression that are, in fact, heritable!

12 Doug Brutlag 2011 DNA Methylation & the Epigenetic Code Paula Vertino, Henry Stewart Talks

13 Doug Brutlag 2011 DNA Methylation & Histone Modifications Form the Epigenetic Code Paula Vertino, Henry Stewart Talks

14 Doug Brutlag 2011 Methylation of Cytosine in DNA Paula Vertino, Henry Stewart Talks

15 Doug Brutlag Methyl Cytosine in DNA Paula Vertino, Henry Stewart Talks

16 Doug Brutlag 2011 Cytosine Methylation Maintains Inactive-Condensed Chromatin State Transcription factors RNA polymerase Transcription Acetylation DNA methyltransferase 5-methyl-C Methyl-CpG Binding proteins and associated co-repressors Histone deacetylase Transcription blocked X Deacetylation Chromatin compaction Transcriptional silencing Alex Meissner, Henry Stewart Talks

17 Doug Brutlag Methyl Cytosine is Found in Heterochromatic Regions John Greally, Henry Stewart Talks

18 Doug Brutlag 2011 Structure & Epigenetics of Euchromatin versus Heterochromatin Paula Vertino, Henry Stewart Talks Me

19 Doug Brutlag 2011 Maintenance of Cytosine Methylation Alex Meissner, Henry Stewart Talks

20 Doug Brutlag 2011 Passive Demethylation of 5-Methyl-Cytosine Alex Meissner, Henry Stewart Talks

21 Doug Brutlag 2011 Establishment and Maintenance of Cytosine Methylation Alex Meissner, Henry Stewart Talks

22 Doug Brutlag 2011 Some DNA Methyl Transferases are Essential Alex Meissner, Henry Stewart Talks

23 Doug Brutlag 2011 Some DNA Methyl Transferases are Essential Alex Meissner, Henry Stewart Talks

24 Doug Brutlag 2011 Methylated DNA from Zygote to Adult Alex Meissner, Henry Stewart Talks

25 Doug Brutlag 2011 Methylated DNA from Zygote to Adult Alex Meissner, Henry Stewart Talks

26 Doug Brutlag 2011 DNA Methylation Differentiates Totipotent Embryonic Stem Cells from Unipotent Adult Stem Cells Alex Meissner, Henry Stewart Talks

27 Doug Brutlag 2011 DNA Methylation Differentiates Totipotent Embryonic Stem Cells from Unipotent Adult Stem Cells Alex Meissner, Henry Stewart Talks

28 Doug Brutlag 2011 DNA Methylation Differentiates Totipotent Embryonic Stem Cells from Unipotent Adult Stem Cells Alex Meissner, Henry Stewart Talks

29 Doug Brutlag 2011 Differentiated Cells can Become Totipotent Alex Meissner, Henry Stewart Talks

30 Doug Brutlag 2011 Critical CpG Sequences in CpG Islands Near Promoters Alex Meissner, Henry Stewart Talks

31 Doug Brutlag 2011 Organization of the Epigenome Paula Vertino, Henry Stewart Talks

32 Doug Brutlag 2011 Epigenetic Imprinting Marisa Bartolomei, Henry Stewart Talks

33 Doug Brutlag 2011 Epigenetic Imprinting of H19 & Igf2 Loci Marisa Bartolomei, Henry Stewart Talks

34 Doug Brutlag 2011 Insulator Model for the Imprinting of H19 & Igf2 Loci Marisa Bartolomei, Henry Stewart Talks

35 Doug Brutlag 2011 Methylation Changes During Development Marisa Bartolomei, Henry Stewart Talks

36 Doug Brutlag 2011 Demethylation of the Paternal Genome Adrien Bird, Henry Stewart Talks

37 Doug Brutlag 2011 Methylation Changes During Development Paula Vertino, Henry Stewart Talks

38 Doug Brutlag 2011 Methylation Changes During Development Paula Vertino, Henry Stewart Talks

39 Doug Brutlag 2011 Methylation Changes During Development Paula Vertino, Henry Stewart Talks

40 Doug Brutlag 2011 X Chromosome Inactivation: Barr Bodies Barr, M. L., Bertram, E. G., (1949), A Morphological Distinction between Neurones of the Male and Female, and the Behaviour of the Nucleolar Satellite. Nature. 163 (4148): Lyon, M. F., (2003), The Lyon and the LINE hypothesis. j.semcdb 14, (Abstract)

41 Doug Brutlag 2011 X Chromosome Inactivation: CG Island Methylation Adrien Bird, Henry Stewart Talks

42 Doug Brutlag 2011 XIC Region Barbara Migeon, Henry Stewart Talks

43 Doug Brutlag 2011 Characteristics XIST Gene Barbara Migeon, Henry Stewart Talks

44 Doug Brutlag 2011 Xist Works in Cis Barbara Migeon, Henry Stewart Talks

45 Doug Brutlag 2011 Only one X is active Barbara Migeon, Henry Stewart Talks

46 Doug Brutlag 2011 Inactive X has unacetylated histone H4 Barbara Migeon, Henry Stewart Talks

47 Doug Brutlag 2011 Distinguishing features of Xi and Xa Barbara Migeon, Henry Stewart Talks

48 Doug Brutlag 2011 Agouti Genes in Mice Emma Whitelaw, Henry Stewart Talks

49 Doug Brutlag 2011 Epigenetic Inheritance Emma Whitelaw, Henry Stewart Talks

50 Doug Brutlag 2011 Methylation of Agouti Genes in Mice Emma Whitelaw, Henry Stewart Talks

51 Doug Brutlag 2011 Reprogramming of A vy Allele in Development Emma Whitelaw, Henry Stewart Talks

52 Doug Brutlag 2011 Environment can Influence Epigenetic Changes Emma Whitelaw, Henry Stewart Talks

53 Doug Brutlag 2011 Hongerwinter 1944 German’s blocked food to the Dutch in the winter of Calorie consumption dropped from 2,000 to 500 per day for 4.5 million. Children born or raised in this time were small, short in stature and had many diseases including, edema, anemia, diabetes and depression. The Dutch Famine Birth Cohort study showed that women living during this time had children years later with the same problems despite being conceived and born during a normal dietary state.

54 Doug Brutlag 2011 Summary of Epigenetic Gene Regulation Patterns of DNA methylation in adult cells parallels cell fate, chromatin structure and gene activation. Most DNA methylation is removed at fertilization and re-established during embryogenesis. Imprinted genes keep their parental pattern of methylation giving rise to parental patterns of expression. Patterns of histone modifications parallel DNA methylation. Methylated gene regions are genetically inactive, highly condensed and special histone modifications. Active gene regions have little DNA methylation and distinctive histone modifications (acetyl groups and H3K4methyl). X chromosome inactivation in females is correlated with extensive CG island methylation on one chromosome, condensation, inactivation and Barr body formation. Alterations in gene and CG island methylation patterns are seen in aging and in cancer. Most CG islands are not methylated except for X chromosome inactivation and tumor suppressors in cancer.


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