Transcript Epigenetics
Epigenetics Challenging the traditional dogma of human health and disease Epigenetics Definition • Stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence. • A change in phenotype without a change in genotype. • A study of the mechanisms that switch genes on and off. https://en.wikipedia.org/wiki/Epigenetics . Accessed 09/19/2016 Epigenome • Epigenetic mechanisms operate at the transcriptional and posttranscriptional level of gene activity as well as at the level of protein translation and posttranslational modifications. • Mechanisms include: – – – – DNA methylation Histone modifications ncRNA modifications Chromatin remodeling https://www.genome.gov Epigenetic Modifications • DNA methylation – Important regulator of gene transcription – Methylation occurs at the DNA and histone level https://www.whatisepigenetics.com Epigenetic Modifications • Histone modification – Covalent post-translational modification to histone proteins. – Can impact gene expression by altering chromatin structure. – Affects gene expression regulation https://www.whatisepigenetics.com https://www.whatisepigenetics.com Epigenetic Modifications • Non-coding RNA – RNA that is not translated into proteins. – Interacts with mRNA and may prevent protein translation. – Regulates gene expression at the transcriptional and post transcriptional level. https://www.whatisepigenetics.com Epigenetic Modifications • Chromatin Remodeling – Alterations to histone proteins contribute to the accessibility and compactness of chromatin. https://www.whatisepigenetics.com Epigenetic Associated Diseases Epigenetic Mechanism Disease Aberrant DNA Methylation (hyper and hypomethylation) Cancer • Bladder, lymphomas, ovarian, medulloblastoma, colorectal, breast, acute myeloid leukemia, Barret’s adenocarcinoma, melanoma, gastric, cervical, squamous cell lung. Autoimmune • Systemic lupus, erythematosus, subacute cutaneous lupus erythematosus, scleroderma, inflammatory skin disease. Imprinting Disorders • Beckwith-Wiedemann syndrome, Russel-Silver syndrome, transient neonatal diabetes. Neurodegenerative Disorders • Alzheimer’s, Parkinson’s. Aberrant Histone Modifications Cancer • Gastric, colorectal, non-small-cell lung cancer, prostrate, pancreatic, papillary neoplasm, lung adenocarcinoma. Autoimmune • Lupus. Neurodegenerative Disorders • Huntington’s disease, schizophrenia. Cardiovascular Diseases • COPD Aberrant miRNA (ncRNA) Expression Cancer • Esophageal squamous cell carcinomas, lung, primary head and neck squamous cell carcinoma, gastric, prostate, melanoma, hepatocellular. Epigenetic Technologies • Next-gen sequencing techniques – DNA methylation • Bisulfite sequencing (Bi-seq) and reduced –representation Bi-seq (RRBS). • Methylated DNA immunoprecipitation sequencing (MeDIP-seq), methylated DNA capture by affinity purification sequencing (MeCAPseq), and methylated DNA binding domain sequencing (MBD-seq). • Methylation-sensitive restriction enzyme sequencing (MRE-seq) – Histone modification • Chromatin immunoprecipitation followed by sequencing (ChIP-seq) – Non-coding RNAs • Detection using RNA-sequencing studies – Chromatin structure assays • DNase I hypersensitivity site sequencing (DNase-seq), formaldehydeassisted isolation of regulatory elements followed by sequencing (FAIRE-seq), sonication of cross-linked chromatin followed by sequencing (Sono-seq), and chromosome conformation capture sequencing (3C-seq). Epigenetic Research in Human Disease http://learn.genetics.utah.edu/content/epige netics/twins/ http://learn.genetics.utah.edu/content/epige netics/twins/ Monozygotic twins Ramon, Romolo, Joey and David Agouti twin mice. Digital image. <http://www.pbs.org/wgbh/nova/body/epige netic-mice.html> Epigenetics “In biology, Darwin and Mendel came to define the nineteenth century as the era of evolution and genetics. Watson and Crick defined the twentieth century as the era of DNA, and the functional understanding of how genetics and evolution interact. But in the twenty-first century, it is the new scientific discipline of epigenetics that is deconstructing so much of what we took as dogma and rebuilding it in an infinitely more varied, more complex, and even more beautiful fashion.” http://www.naturalhistorymag.com/features/142195/beyond-dnaepigenetics/accessed 11/09/2016 References • • • • • • • • • • • • https://en.wikipedia.org/wiki/Epigenetics accessed 9/19/2016 http://www.whatisepigenetics.com/what-is-epigenetics/ accessed 09/19/2016 https://www.genome.gov/27532724/epigenomics-fact-sheet/ accessed 09/20/2016 http://learn.genetics.utah.edu/content/epigenetics/intro/ accessed 09/19/2016 Bell, Spector, A twin approach to unraveling epigenetics. Trends in Genetics. 2011 Mar; 27(3); 116-125 http://www.whatisepigenetics.com/fundamentals/ accessed 09/20/2016 Haluskova, J., Epigenetic Studies in Human Diseases. Folia Biologica (Praha) 56, 8396 (2010) Shuk-Mei Ho, Abbey Johnson, Pheruza Tarapore, Vinothini Janakiram, Xiang Zhang, and Yuet-Kin Leung. Environmental Epigenetics and Its Implication on Disease Risk and Health Outcomes. ILARJ. 2012;53(3-4):289-305 http://www.whatisepigenetics.com/dna-methylation/ accessed 9/21/2016 http://www.whatisepigenetics.com/chromatin-remodeling/ accessed 9/23/2016 http://learn.genetics.utah.edu/content/epigenetics/twins/ accessed 09/26/2016 http://www.naturalhistorymag.com/features/142195/beyond-dnaepigenetics/accessed 11/09/2016