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Thomas Evans

on 9 June 2013

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Transcript of Epigenetics

Ethics New regulations meant to create a more ethically aware society by making environmental factors with epigenetic effects more known to individuals.
Federal environmental regulatory statutes require assessments for risks to health
Clean Air Act (CAA), Clean Water Act (CWA), Toxic Substances Control Act (TSCA), Resource Conservation and Recovery Act, (RCRA), Safe Drinking Water Act (SDWA), and the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA)
Food and Drug Regulation
Epigenetics Discrimination: prohibiting fertile women from being hired; whether it constitutes a disability under the Americans with Disabilities Act (ADA) DNA Methylation Epigenetics The Epigenome and Applications Epigenome consists of chemical compounds that modify, or mark, the genome in a way that tells what, where, and when a task should be done. The marks, not part of the DNA, can be passed on during division from one generation to the next.
Development of diagnostic tools to assess if other diseases are caused by epigenetic alterations: Epigenetic therapy
Ability to detect epigenetic patterns of gene inactivation and develop drugs that interact with tumors that proliferate due to epigenetic silencing
To date, most attention has centered on therapies that reverse methylation as a means of switching on genes that will suppress tumor growth or modify sensitivity to existing therapies Cancer Screening & Gene Expression Mapping Future Advancements DNA methylation patterns will serve important purposes in the care and management of cancer patients, i.e. early non-invasive diagnosis of cancer
Ideal scenario: a robust means of identifying epigenetic inactivation as a major characteristic in a tumor and to provide a personalized treatment for that patient.
DNA methylation status may be useful as a biomarker of toxicity
PCR amplification of DNA treated with sodium bisulfite allows the characterization of DNA methylation in tumors and requires limited patient tissue
PCR amplification using two types of primers will distinguish between methylated or unmethylated DNA PacBio RS II is a Single Molecule, Real-Time (SMRT®) DNA Sequencing System that provides the highest consensus accuracy and longest read lengths of any available sequencing technology.
To overcome the challenges inherent in observing an enzyme that is 15 nanometers, or nm, in diameter running in real time, they developed three key innovations:
The SMRT Cell
Phospholinked nucleotides
The PacBio RS II Epigenetics: studies the phenotypic expression of genes from environmental factors that can alter genetic expression without physically changing the DNA sequence
gene expression is regulated by histone modification, DNA methylation/acetylation/phosphorylation, and other transcription factors
Transciptional proteins help maintain and ultimately determine the higher order of the chromatin; shape and structure is essential to specific gene expression or repression
the genetic mechanisms can be influenced by outside factors determining gene transcription: stress, diet, fetal factors, and chemicals
Epigenetic influences can promote and cause major diseases that include cancer, syndromes involving chromosomal instabilities, and mental retardation DNA and Epigenetics Prior to Epigenetic Research Technology Platform PCR (Polymerase chain reaction): laboratory technique used to amplify DNA sequences. Uses short DNA sequences called primers to select the portion of the genome to be amplified. The temperature of the sample is repeatedly raised and lowered to help a DNA replication enzyme copy the target DNA sequence. Can produce a billion copies of the target sequence in just a few hours. 1) denaturation 2) annealing 3) elongation
Methylation mapping: uses bisulfite sequencing to convert unmethylated cytosine into uracil, leaving methylated ones untreated. Amplification and sequencing of both sequences leads to identification of methylated sites; further advancements allowed for genome-wide sequencing, reducing limitations
Chromatin Analysis: observation of genome-wide chromatin interaction and histone modifications at varying genomic locations; determination of inactive sights along DNA sequences One of the most important contributions to the study of the human body and genetic research was the sequencing of the human genome (HGP)
traditional chemotherapy and the treatment of other diseases have been limited in their approach and route, but nevertheless still ongoing
chemotherapeutic agents, radiation, and surgery with unfortunate disadvantages to these treatments that contribute to the degrading of the patient's immune system and overall physical integrity
chemotherapy not only kills rapidly dividing cancer cells but also normal cells that divide rapidly Contributes to genetic imprinting, an inheritable process where one of the two alleles of a gene is silenced due to an epigenetic process
Mapping of methylations in DNA are most commonly and easily observable form of epigenetic change
The addition/removal of methyl group from a cytosine or adenine DNA nucleotides; unidirectional change that can also contribute to chromatin structure
inhibited binding of transcription proteins; leads to binding of methyl-binding domain proteins
At least three of the five known members of this family (MeCP2, MBD2, MBD3) have been shown to be associated with large protein complexes containing histone deacetylase (HDAC1 and HDAC2) and chromatin-remodeling activities (sin3a and mi-2). Thus, DNA methylation has a direct influence on both histone acetylation and higher-order chromatin structure [2] Cancer: almost all human cancer types appear to show a loss of the normal control of DNA methylation and an overall decreased level at a genome wide level
Azacitidine, approved for myelodysplastic syndrome. The drug turns on genes shut off by methylation. The drug’s epigenetic function doesn’t make it a “miracle drug,” however.
15% benefit
serious side effects: nausea (71%), anemia (70%), vomiting (54%), and fever (52%).
Genes are re-expressed by gene re-introduction, they can lead to suppression of tumor growth or sensitization to existing therapies
"Re-expression of genes epigenetically inactivated can result in the suppression of tumour growth or sensitization to other anticancer therapies." [1] “However, the evidence is still far too thin to form a basis for any overarching theories about which substances and which target genes are most likely to mediate adverse effects of the environment on diseases, says Melanie Ehrlich, a biochemistry professor at the Tulane University School of Medicine and Tulane Cancer Center” [2] The Science of Change Genome-wide DNA methylation, hydroxymethylation, targeted sequencing for DNA methylation analysis, chromatin analysis & bioinformatic services
This platform can be used to detect 3-4 million unique CpG sites, allowing >85% coverage of all CpG islands and >80% of all gene promoters for a maximal amount of methylation data from less sequencing reads, reducing the overall cost. The system is conducive to biomarker discovery by providing for the identification and analysis of differentially methylated regions (DMRs) between samples. Histone modification: proposed to affect chromosome function through at least two distinct mechanisms: 1) Modifications can alter the electrostatic charge of the histone causing a structural change in histones or their binding to DNA. 2) These modifications are binding sites for protein recognition modules, such as the bromodomains or chromodomains, that recognize acetylated lysines or methylated lysine
If changes in histones can influence DNA methylation, then it is possible that the methylation of genes observed in tumors is a result of transcriptional silencing owing to histone modification or chromatin remodelling, rather than of DNMT activity
Chromatin modification: tight, bound complex structure of DNA and proteins fit within the nucleus; alteration of complex by acetyl groups, enzymes, specific RNA like siRNA will influence gene expression Histone Modification aim to generate tissue-specific DNA methylation reference profiles of the human genome.
The chosen approach involved treatment of the genomic DNA with sodium bisulphite which converts unmethylated cytosines into uracil but does not affect methylated cytosines.
Following PCR amplification and sequencing of selected amplicons from bisulphite-converted DNA, the degree of methylation was determined by comparison of the corresponding signal ratios at CpG dinucleotides, the predominant sites of DNA methylation.
The Human Epigenome Consortium is a public/private collaboration that aims to identify and catalogue Methylation Variable Positions (MVPs) in the human genome. References: [1]: Brown, Robert, and Gordon Strathdee. "Epigenomics and Epigenetic Therapy of Cancer." Rev. of Trends in Molecular Medicine. SciVerse 1 Apr. 2002: n. pag. Print.
[2]: "DNA Methylation Patterns and Epigenetic Memory." DNA Methylation Patterns and Epigenetic Memory. N.p., n.d. Web. 30 Apr. 2013. <http://genesdev.cshlp.org/content/16/1/6.short>.
[3]: "Epigenomics and Epigenetics Research." - EGRP. N.p., n.d. Web. 30 Apr. 2013. <http://epi.grants.cancer.gov/epigen.html>.
"Pacific Biosciences." : Base Modification Detection. N.p., n.d. Web. 03 May 2013. [4]:<http://pacb.com/applications/base_modification/index.html>.
Rothstein, Mark A. "Ethical Implications of Epigenetics Research." Nature Reviews: Genetics. Nature Publishing Group, n.d. Web.
[5]: Rothstein, Mark, Yu Cai, and Gary Marchant. "THE GHOST IN OUR GENES: LEGAL AND ETHICAL IMPLICATIONS OF EPIGENETICS." (2009): n. pag. Print.
[6]: Roukos, Dimitrios. "Next-generation Sequencing and Epigenome Technologies: Potential Medical Applications." Editorial. Expert Reviews 2012: 723-26. Web. 30 Apr. 2013. <http://www.expert-reviews.com/doi/pdf/10.1586/erd.10.68>.
[7]:Weinhold, Bob. "National Center for Biotechnology Information." National Center for Biotechnology Information. U.S. National Library of Medicine, 25 Aug. 2005. Web. 27 May 2013.
[8]; Egger, Gerda. "Epigenetics in Human Disease and Prospects for Epigenetic Therapy." Nature (2004): n. pag. Nature. Web. 25 May 2-13. <http://www.nature.com/nature/journal/v429/n6990/full/nature02625.html>. Thomas Evans, Jonathan Bird & Michael George
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