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The Emerging Role of Epigenetics in Human Diseases David P. Gardner, Ph.D. Professor of Biochemistry.

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Presentation on theme: "The Emerging Role of Epigenetics in Human Diseases David P. Gardner, Ph.D. Professor of Biochemistry."— Presentation transcript:

1 The Emerging Role of Epigenetics in Human Diseases David P. Gardner, Ph.D. Professor of Biochemistry

2 Objectives  Provide a working definition of epigenetics and contrast an epigenetic change with a mutation.  Contrast the normal process of genomic imprinting with abnormal changes in epigenetic tags seen in several diseases described.  Describe evidence that nutritional status can influence the epigenetic profile of later generations.  Illustrate and describe epigenetic tags involving cytosine methylation and histone acetylation.  Describe the mechanism of action of Vorinostat.  Interpret the divergence of epigenomes of identical twins with respect to potential difference in disease presentation between twins.

3 Epigenetics  Epigenetics literally means ‘above’ the genetics.  Has had multiple definitions over time.  2008 Cold Spring Harbor Epigenetics meeting:  “An epigenetic trait is a stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence.”  Alterations in the DNA sequence = mutations

4 Epigenetic Research  The number of publications in the field has increased dramatically in the last 10 years. Genetic Engineering and Biotechnology News Feb 1, 2013 (Vol. 33, No. 3)

5 Epigenetic Effects  The effects of epigenetics have been known for many years.  Lyon Hypothesis from 1961.  Renamed the Lyon Law in 2011.  Inactive X chromosome is heavily epigenetically modified.

6 Another Familiar Epigenetic Case  Prader-Willi Syndrome  Angelman Syndrome  Chromosome 15 imprinting

7 Angelman/Prader-Willi  Commonly referred to as genomic imprinting.  Imprinting is not the cause of these syndromes but is responsible for the unique presentation of these diseases.

8 Genomic Imprinting  With genomic imprinting, it is thought that the maternal or paternal imprint is erased with each succeeding generation (meiotic division).  A male receives a maternally imprinted and paternally imprinted chromosome 15 but will always transmit a paternally imprinted chromosome 15.  Note that the maternal/paternal imprinting is heritable through mitosis. * Germ Cells Somatic Cells * * *** *

9 Genomic Imprinting  Importantly, X-inactivation and genomic imprinting are normal processes.  Much of the recent research has analyzed when the process of epigenetics is altered from normal.  This has involved the study of changes within somatic cells in disease.  It has also involved the study of changes within the germ cells (heritable epigenetics).

10 Heritable Epigenetics  Evidence suggests that environmental information could be propagated through meiosis.  Studies of Dutch famine of 1944.  Famine during last two trimesters of pregnancy:  8-9% decrease in child’s birth weight (SGA).  Offspring of these SGA children tended to be normal size.  Famine early in pregnancy but not late:  Normal size infants were born.  Offspring of these non-SGA children exhibited high rate of SGA.

11 Överkalix Study  Retrospective study conducted in Överkalix, Sweden.  Divided population into three cohorts: Born 1890 Born 1905 Born 1920 Assessed each cohort for access to food during slow growth period (SGP) of adolescence (8-10 girls, 9-12 boys). Cardiovascular and diabetes mortality determined by nutrition during parents' and grandparents' slow growth period. Kaati G, Bygren LO, Edvinsson S. Eur J Hum Genet. 2002, 10:682-8.

12 Överkalix Study Results  When the father (P=0.05) was exposed to a famine during his SGP, his offspring exhibited protection against cardiovascular causes of death.  Paternal grandmother exposure to famine also showed a trend (P=0.11) towards similar protection in grandchildren.  If the paternal grandfather lived through a famine during his SGP it tended to protect grandchildren from diabetes (P=0.09).

13 Överkalix Study Results  If the paternal grandfather had an abundance of food during their SGP, their grandchildren had a four-fold increased risk for death of diabetes mellitus.  One mechanism to explain these results is transmission of epigenetic markers that were influenced by the environment of the parent.  Effect on grandchildren suggests the markers are maintained through multiple generations.

14 Lamarkism?  Jean Batiste Lamark (1744-1829)  Inheritance of acquired characteristics.  Largely discounted with Darwin’s publication of Origin of Species and the rediscovery of work of Mendel.  Recent work in epigenetics suggest Larmark may have been correct to some degree.

15 Molecular Basis of Epigenetics  Two primary mechanisms identified.  Methylation of cytosine nucleotides in DNA  Posttranslational modification to histone proteins.  Includes acetylation, methylation and phosphorylation  A third proposed mechanism involves expression of small interfering RNAs (siRNA).

16 Cytosine Methylation  Methylation of cytosine occurs at CpG dinucleotides.  Often located just upstream of genes (promoter regions).  Associated with attenuation of expression of nearby genes.

17 Histone Modification  Histones are the proteins that organize the genetic material.  Have a high percentage of basic amino acids, which gives histones an overall positive charge.  Positively charged amino acids associate with the overall negative charge of the DNA.

18 Histone Modification  Most histone modification occurs on the extended tails of histone proteins.  Modifications influence the association of histones with the DNA and patterns of gene expression.  Best studied modification is histone acetylation.

19 Histone Acetylation  Two enzyme types involved in histone acetylation  HAT: histone acetyltransferase  HDAC: histone deacetylase Note that acetylation eliminates the positive charge from the amino acid. It is thought that this changes the chromatin conformation to a form more open to transcription. acetylation = gene expression.

20 HAT/HDAC and Hydrophobic Hormones  It is thought that hydrophobic hormones like thyroid hormone and glucocorticoid influence gene expression by binding to either HDAC or HAT proteins. acetylation = gene expression.

21 Epigenetic Errors  Fragile X syndrome is most commonly caused by a CGG trinucleotide repeat expansion in the 5’ region of the FMR1 gene.  Unaffected individuals have 6-50 CGG repeats.  >200 CGG repeats is seen in individuals with fragile X.  >200 CGG repeats is correlated with hypermethylation at CpG dinucleotides and silencing of the FMR1 gene.

22 Epigenetics and Cancer  DNA repair is a critical process to maintain genomic fidelity.  Loss of DNA repair is thought to be a major contributor to the development of cancer.  Epigenetic changes involving DNA repair genes are thought to be a major early step in cancer progression.  ~13% of sporadic breast cancers and 5-30% of ovarian cancers present with hypermethylation of the BRCA1 gene.  40-90% of sporadic colorectal cancer has hypermethylation of the MGMT gene (O 6 -methylguanine methyltransferase).

23 Therapies Targeting Epigenetic Errors  In contrast to mutations, epigenetic changes can be reversed.  Are there therapies that influence epigenetic patterns?  Yes  Vorinostat (trade name Zolinza) approved by FDA for cutaneous T cell lymphoma in 2006.  Vorinostat is a histone deacetylase inhibitor.  acetylation = gene expression. X X

24 Combination Therapy  Phase III Clinical Trial  Vorinostat plus cytarabine and idarubicin.  85% remission rate after initial treatment.

25 Our Epigenome  If epigenetic markers are dynamic and respond to environmental influences, do they change over time?  Evidence suggests the answer is yes.  Twin studies have been highly informative for this question.

26 Author Statement  “We found that, although twins are epigenetically indistinguishable during the early years of life, older monozygous twins exhibited remarkable differences in their overall content and genomic distribution of 5-methylcytosine DNA and histone acetylation, affecting their gene-expression portrait.”

27 Chromosomal Level  Comparative genomic hybridization for methylated DNA  Yellow = similar chromosome methylation pattern between twins.  Red = regions of hypomethylation in one twin compared to the other.  Green = regions of hypermethylation in one twin compared to the other.

28 Epigenomic Alterations  If the epigenome changes as we age, what kinds of things can induce these changes?  Very active area of current research.  Some interesting findings:  Fear conditioning induces changes in DNA methylation in the brain derived neurotrophic factor (BDNF) gene promoter region in hippocampal neurons of rat brains.

29 Epigenomic Alterations  In rats, social deprivation during the 1 st postnatal week triggers changes in DNA methylation across the BDNF gene.  This was later associated with decreased BDNF gene expression in the prefrontal cortex of adult experimental animals.  A schizophrenic-type state can be induced in mice when they are chronically given l-methionine (substrate for methyltransferase enzymes).  Studies with cocaine exposure suggest that the drug induces acetylation of the BDNF gene histones that is transmittable to future male offspring.

30 Epigenetics and Osteopathic Manipulation  Is it plausible that osteopathic manipulation could influence gene expression through modulation of epigenetic tags on treated tissue?

31 Summary  Epigenetic traits are heritable phenotypes resulting from changes in chromosomes that do not involve changes in DNA sequence.  Scientific and medical interest in epigenetics has increased dramatically in recent years.  Two prominent epigentic mechanisms involve DNA methylation (gene silencing) and histone acetylation (gene activation).  Errors in epigenetic patterns can influence the presentation of human diseases including cancer.  The epigenome changes as we age and can be influenced by the environment.  Drugs that influence the epigenome represent a major area of current research.

32 References  Berger, S.L. et. al. 2009. An operational definition of epigenetics. Genes Dev. 23, 781-783.  Kaati, G. et. al. 2002. Cardiovascular and diabetes mortality determined by nutrition during parents' and grandparents' slow growth period. Eur. J. Hum. Genet. 10 682-688.  Esteller, M. et. al. 2000. Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst. 92, 564-569.  Shen, L. et. al. 2005. MGMT promoter methylation and field defect in sporadic colorectal cancer. J Natl Cancer Inst. 97, 1330-1338.  Garcia-Manero, G. 2012. Can we improve outcomes in patients with acute myelogenous leukemia? Incorporating HDAC inhibitors into front-line therapy. Best Pract Res Clin Haematol. 25, 427-435.  Fraga, M.F. et al. 2005. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A. 102,10604-10609.  Roth, T.L. et. al. 2009. Lasting epigenetic influence of early-life adversity on the BDNF gene. Biol Psychiatry. 65 760-769.  Vassoler, F.M. 2013. Epigenetic inheritance of a cocaine-resistance phenotype. Nat. Neurosci. 16, 42-47.

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