UNCChapel Hill Superfund Research Prog Assessing biological responses
UNC-Chapel Hill Superfund Research Prog Assessing biological responses to contaminants An introduction to epigenetics & the exposome
Same genes, different phenotypes How?
Lesson: DNA Wrap-Packaging Matters Learning Objectives Define the make-up of chromatin Define epigenetics Describe DNA methylation as a means of inhibiting transcription Evaluate impact of environmental agent on gene expression (in mice)
Condensed Chromatin Hydrogen Bonds (between bases) Decondensed Chromatin Nucleotide (consists of a base, a 5 -carbon sugar, and a phosphate group) Phosphodiester Bond (between adjacent nucleotides) http: //commons. wikimedia. org/wiki/File: Chromosom
Genome vs epigenome Genome Genes Hardware Static Epigenome Accessibility to genes Software Plastic
What is Epigenetics? 6 Refers to changes in gene expression caused by mechanisms other than changes in the underlying DNA sequence. “The study of stable alterations in gene expression potential that arise during development and cell proliferation” (Nature). Enables a cell/organism to respond to its dynamic external environment during development and throughout life!
The Epigenome at a Glance Genetic Science Learning Center, University of Utah
Now it appears that our diets and lifestyles can change the expression of our genes. How? By influencing a network of chemical switches within our cells collectively known as the epigenome. NOVA’s Ghost in Your Genes (2006)
Epigenetic Mechanisms 1. DNA Methylation 2. Histone Modification 3. Small, noncoding RNAs (e. g. , micro RNA)
2. DNA methylation 10 The addition of methyl groups to DNA, mostly at Cp. G sites, to convert cytosine to 5 -methylcytosine. SAM 5’ 3’ C G T A C A C G A T G C A T G T G C T A 3’ 5’
DNA methylation is preserved during DNA replication
DNA methylation leads to gene silencing Target gene expressed in normal cell Normal State RNA pol TF Target gene expressed Promoter Epigenetic Modificatio n Target gene inactivated by DNA methylation TF Promoter X Target gene not expressed
1) Changes to DNA Methylation leads to gene silencing Normal State RNA pol Target gene expressed in normal cell e. g. , tumor suppresor gene TF Target gene expressed Promoter Disease State arising from Epigenetic Modificatio Target gene inactivated by hypermethylation TF Promoter X Target gene not expressed
2) Changes to DNA Methylation leads to gene activation Normal State TF Target gene silenced by methylation e. g. , oncogene Promoter Disease State arising from Epigenetic Modificatio X Target gene not expressed Target gene activated by hypomethylation RNA or demethylation pol TF Promoter Target gene expressed
HOW did these mice become different? NOVA’s A Tale of Two Mice Chapters 2 &3
In 2003, a research team at Duke discovered HOW changing the diet of Agouti yellow female mice resulted in genetically identical offspring with altered coat color distribution and disease susceptibility.
Agouti mouse model Avy = Agouti Viable Yellow Dominant allele; paternally inherited Allele is always expressed Genetically identical except for agouti gene a = mutant version of agouti gene ?
Ge Genetically Identical Siblings Environmental epigenomics and disease susceptibility Randy L. Jirtle and Michael K. Skinner Nature Reviews Genetics 8, 253 -262 (April 2007) http: //www. nature. com/nrg/journal/v 8/n 4/fig_tab/nrg 2045_F 2. html Epigenetic Variation
The most important effect of epigenetic marks – maybe their reason for existing – might be to wildly expand the number of variant individuals in a population. Michael Skinner, A New Kind of Inheritance (2014)
In this mouse model, a shift in coal color distribution indicates changes in epigenetic modi Environmental epigenomics and disease susceptibility Randy L. Jirtle and Michael K. Skinner Nature Reviews Genetics 8, 253 -262 (April 2007) http: //www. nature. com/nrg/journal/v 8/n 4/fig_tab/nrg 2045_F 2. html
Dr. Jirtle's pioneering work in epigenetics and genomic imprinting has uncovered a vast territory in which a gene represents less of an inexorable sentence and more of an access point for the environment to modify the genome. TIME MAGAZINE, PERSON OF THE YEAR 2007
Experiment: Does a maternal diet with soy influence expression of the agouti gene? Female mice were fed genistein, the major phytoestrogen in soy, before and during pregnancy.
Shift in coat color distribution… Genetically identical offspring exhibited varying coat colors.
23% Environmental epigenomics and disease susceptibility Randy L. Jirtle and Michael K. Skinner Nature Reviews Genetics 8, 253 -262 (April 2007) http: //www. nature. com/nrg/journal/v 8/n 4/fig_tab/nrg 2045_F 2. html 50%
Experimental results
Conclusions Read the authors’ conclusions and with a partner discuss how these conclusions could be relevant for humans. Genetic Science Learning Center, University of
Conclusions Our diet, especially during pregnancy, can influence our epigenome and ultimately determine our susceptibility to cancer and disease. Genetic Science Learning Center, University of
But nurture matters too. Many of the contingencies of life- what we eat, what pollutants are in our environment, how often we are stressed – affect how the genes operate. Michael Skinner, A New Kind of Inheritance (2014)
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Epigenetics and fetal development “Epigenetics is being considered an important mechanism through which various stressors can operate. Many lines of evidence point to their being a special concern during rapid fetal development. ” Frederica Perera, Columbia Center for Children’s Environmental Health
Inheritance of Epigenetic modifications Multigenerational Inheritance from parent to progeny Meiotic or transgenerational Inheritance by F 3 offspring (rare; not documented in human studies to date) Vinclozolin exposure and ra
To demonstrate transgenerational epigenetic inheritance researchers must: • Rule out the possibility of genetic changes; and, • Show that the epigenetic effect can pass through enough generations (F 3 or great grandchild) to Genetic Science Learning Center, University of rule out the possibility
Contact Information Superfund Research Program University of North Carolina at Chapel Hill http: //www. sph. unc. edu/srp/ Resources > For educators Research Translation Core Dana Haine dhaine@unc. edu (919) 843 -5735
If time permits…
Imprinting 36 Genomic imprinting is a genetic phenomenon by which certain genes are expressed in a parent-oforigin-specific manner It is an inheritance process independent of the classical Mendelian inheritance. The first naturally occurring example of an imprinted gene was the discovery of imprinting in the IGF-2 gene in mice in 1991, and currently about ~150 imprinted genes have been identified in mice and humans.
DNA methylation & imprinting 37 Imprinted genes are inactive due to DNA methylation. For imprinted genes, only one gene copy is active http: //learn. genetics. utah. edu
DNA methylation & imprinting 38 Imprinted genes are protected from reprogramming that occurs in zygote http: //learn. genetics. utah. edu
The Environment & Imprinted Genes Environmental signals can affect the imprinting process during gamete development Imprinted genes in the adult are sensitive to environmental signals (since only one gene copy is active)
Imprinting: an inheritance process independent of Mendelian inheritance
Why Imprint? The Genetic Conflict Hypothesis 41 Many imprinted genes are involved in growth and metabolism. Often maternally and paternally imprinted genes work in the very same growth pathways. This conflict of interest sets up an epigenetic battle between the parents -- a sort of parental tug-of-war.
Acetylation is the most highly studied 42
3. Non-protein coding RNAs 43 short, non-coding RNAs � e. g. , micro. RNAs partially complementary to one or more m. RNA molecules post-transcriptional gene regulation, typically down regulation
1. Histone modification 44 If the way that DNA is wrapped around the histones changes, gene expression can change. Histone Modification http: //ehp. niehs. nih. gov/wp-content/uploads/2012/09/WP_Focus_2_Title_web. png
Post-translational histone modifications
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