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1 EPIGENETICS

2 What is Epigenetics? The study of environmental factors on gene expression in DNA. The molecule is called methylation controls when genes are turned on. Methylation turns off genes. Acetylation turn genes on.

3 What is Epigenetics? Watch the video

4 History of Epigenetics Discovered by Paul Kammerer, a lamarckian evolutionist, in the 1920s. The midwife toad experiment was controversial and soon found to have been fraudulent. Recent review of his experiment has shown it to be possible.

5 Epigenetic Inheritance Genetic tags are passed down through generations When the zygote is formed many epigenetic tags are removed from the chromosomes of the parents, but some remain

6 Epigenetic Inheritance cont. Previously believed that genetic information was passed through DNA only Studies in the field of epigenetics shows that parent s experiences are passed on to offspring through epigenetic tags

7 Identical Twins Identical twins are from the same zygote, so they begin life with the same genetic information, including epigenetic tags While infants they experience the same or very similar environments, so there is little variation in the epigenome Over time the twins environments will diverge, resulting in individual epigenetic tags to form for each twin

8 Identical Twins cont. The difference in the twins epigenomes is what makes them become different when they are older The epigenetic tags can have such an effect on the twins that one can develop a disease while the other is fine When this situation occurs, researchers will try to pinpoint the environmental factors that are responsible for the disease

9 Environmental Factors The major factors that affect the epigenome are: Stress Social interactions Physical activity Exposure to toxins Diet No specified yet The nutrition of the mother can affect the epigenome of a fetus Stress hormones also travel from the mother to a fetus to affect the epigenome

10 There is significant phenotypic discordance: Mental disorders Cancer Monozygous twins share a common genotype and are genetically identical

11

12 Agouti Twin Sisters

13

14 Coat Colors of Genetically Identical Agouti Mice Liter Mates

15 Coat color serves as a sensor for the degree of methylation present

16

17

18 Mosaicism: An Individual with Two Different Eye Colors Diego

19 Mosaicism: An Individual Eye with Two Colors

20 Bisphenol A

21 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? Myoblasts can only form muscle cells Keratinocytes only form skin cells Hematopoetic cells only become blood cells 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!

22 What is Epigenetics? Epigenetics refers to the study of changes in the regulation of gene activity and expression that are not dependent on gene DNA sequence Epigenetics is the study of environmental factors on gene expression in DNA. Methylation turns off genes. Acetylation turn genes on. While epigenetics often refers to the study of single genes or sets of genes, epigenomics refers to more global analyses of epigenetic changes across the entire genome.

23 Three Levels of Folding of DNA in Chromatin

24 Methylated DNA from Zygote to Adult

25 DNA Methylation Differentiates Totipotent Embryonic Stem Cells from Unipotent Adult Stem Cells

26 DNA Methylation Differentiates Totipotent Embryonic Stem Cells from Unipotent Adult Stem Cells

27 DNA Methylation Differentiates Totipotent Embryonic Stem Cells from Unipotent Adult Stem Cells

28 Differentiated Cells can Become Totipotent

29 Critical CpG Sequences in CpG Islands Near Promoters

30 Organization of the Epigenome

31 Epigenetic Imprinting

32 Methylation Changes During Development

33 Epigenetics Mechanisms RNA Interference Gene Expression Histone Modifications DNA Methylation

34 The term epigenetic It refers to all heritable changes in gene expression and chromatin organization that are independent of the DNA sequence itself.

35 The region of DNA will then be heritably maintained in an inactive state. Transcriptionally active chromatin regions tend to be hyperacetylated and hypomethylated. If a region of DNA or a gene is destined for silencing, chromatin remodeling enzymes such as histone deacetylases and ATP-dependent chromatin remodelers likely begin the gene silencing process. One or more of these activities may recruit DNA methyltransferase resulting in DNA methylation, followed finally by recruitment of the methyl-cpg binding proteins.

36 Methylation of Cytosine in DNA Paula Vertino, Henry Stewart Talks

37 5-Methyl Cytosine in DNA Paula Vertino, Henry Stewart Talks

38 DNA Methylation Hypomethylation Hypermethylation

39 DNA Methylation and Cancer

40 RNA Interference (RNAi)

41 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 reestablished during embryogenesis. Imprinted genes keep their parental pattern of methylation giving rise to parental patterns of expression. Patterns of histone modifications parallel DNA methylation.

42 Summary of Epigenetic Gene Regulation 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.

43 Epigenetics in Medicine Epigenetics can help us master stem cells. With that knowledge we may be able to control changing stem cells. Epigenetics has opened a new field in genetic research.

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