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Introduction to Epigenetics

Introduction to Epigenetics. Manoj Kannan BITS-Pilani & NCI-Frederick. Recap of some familiar terms in genetics. Gene Allele Genotype Phenotype Gene expression Gene silencing Genome. Genome expression. Well-established paradigm of how genetic information is transcribed and translated

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Introduction to Epigenetics

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  1. Introduction to Epigenetics Manoj Kannan BITS-Pilani & NCI-Frederick

  2. Recap of some familiar terms in genetics Gene Allele Genotype Phenotype Gene expression Gene silencing Genome

  3. Genome expression • Well-established paradigm of how genetic information is transcribed and translated • Human genome project has given plenty of data, which is still being mined for useful information • An estimated 140,000 proteins in the human body • Different cells express a different subset of proteins • Yet almost all cells have the same genomic sequence comprised of just under 25,000 genes • 25,000 genes  140,000 proteins?? Simple math doesn’t explain! • Hence, it’s not just the genes, but how they are regulated that explains the phenotype variations

  4. Here is a phenotype variation… What do you think is the basis? But epigeneticallydifferent! ALL THE MICE ARE GENETICALLY IDENTICAL! May be from different parents? Well, age difference… Oh, okay - mutation in the pigment causing gene?

  5. What is Epigenetics? • Study of heritable changes in gene function that do not involve changes to the nucleotide sequence of DNA • When a cell undergoes mitosis or meiosis, the epigenetic information is stably transmitted to the subsequent generation • Epigenetic controls add an ‘extra layer’ of transcriptional control

  6. Three major epigenetic processes we will discuss today… • DNA Methylation • Histone modifications • RNA-mediated phenomena

  7. DNA Methylation Most well-studied epigenetic tag/mark; best understood epigenetic cause of disease Conserved across various kingdoms of life SAM – S-adenosylmethionine SAH – S-adenosylhomocystine So, G, A, T, C…. and the fifth base, mC in mammalian genome

  8. Distribution of DNA methylation • In mammals, in the context of CpG dinucleotides (plants have other types too) • Methylated CpGs are associated with silenced DNA, eg. Transposons, inactive X chromosome, imprinted genes • “CpG islands”, associated with promoters of 40% of mammalian genes, are generally free of methylation eg. housekeeping genes, tissue-specific genes

  9. DNA methyltransferases (DNMTs) 2 major classes of enzymes in mammalian systems De novo methylases Maintenance methylase Mouse knockouts of these genes tell us they are necessary for the survival and proper development of the organism.

  10. Unmethylated (or hypomethylated) promoter allows gene transcription Me-CpG binding proteins also preclude TF binding to the promoter region Methylated CpGs block binding of TFs; hence, transcription blocked How does DNA methylation affect gene transcription? Other ways too…

  11. Role of DNA methylation • Tight control for maintaining gene silencing (vertebrate genes are less “leaky” compared to bacterial) • Transcriptional silencing of transposons (‘genome defense’ model) • Genomic imprinting – one of the alleles of a gene is silenced, depending on the parent of origin • X inactivation – all but one of the X chromosomes in • female is inactivated – methylation of the inactive X copy

  12. Three major epigenetic processes • DNA Methylation • Histone modifications • RNA-mediated phenomena

  13. Structural organization of the genome Unless the genome is accessible by the transcription machinery of the cell, the genome cannot be functional! Hence, the utilization of the biological information in the genome is dependent on the chromatin organization.

  14. ~146 bp DNA Histone octamer core Structure of a nucleosome

  15. Post-translational histone modifications A = acetylation M = methylation P = phosphorylation U = ubiquitination

  16. Consequences of tail modifications • Higher order chromatin structure is affected eg. Addition of acetyl groups (-ve) neutralizes the positive charge on lysine => affinity of the histone to bind tightly to DNA is reduced => chromatin becomes less compact => transcription of the associated gene is favored Vice versa for deacetylation (the gene is repressed) • Other proteins are attracted to these sites of modifications….which, in turn, affect gene expression

  17. Enzymes catalyze these covalent tail modifications • Histone Acetyl Transferases (HATs) function as large, multiprotein complexes, eg. SAGA, ADA complexes (yeast), TFTC complexes (humans); associated with transciptional activation. • Histone Deacetylases (HDACs) part of multiprotein complexes, eg.Sin3, NuRD; associated with transcriptional repression. • Histone Methyl Transferases (HMTs) • Histone Demethylases

  18. Comparing chromatin types

  19. DNA methylation Self-reinforcing repressive cycle Histone deacetylation Histone H3-K9 methylation Crosstalk between DNA methylation and chromatin modification

  20. Three major epigenetic processes • DNA Methylation • Histone modifications • RNA-mediated phenomena

  21. RNA interference (RNAi) causes gene silencing RNAi initiates heterochromatin formation in fission yeast and DNA methylation in plants.

  22. Epigenetics in human disease Association with various cancers – stomach, kidney, colon, pancreas, liver, uterus, lung and cervix ICF syndrome Fragile X syndrome Angelman’s syndrome Rett Syndrome Coffin-Lowry Syndrome HUMAN “EPIGENOME” PROJECT

  23. Epigenetics….Environment

  24. Epigenetics….Environment

  25. Epigenetics….Environment And Consciousness! “The Biology of Belief: Unleashing the Power of Consciousness, Matter and Miracles” is a recent book in the market on epigenetics! Disclaimer: I haven’t read the book yet!

  26. References • Genomes (3/E) – T.A. Brown • Molecular Biology of the Cell (4/E) – Bruce Alberts, et al. • Human Molecular Genetics (2/E) – Strachan & Read • Developmental Biology (7/E) - Gilbert • NCBI Bookshelf - free online books! (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books)

  27. Thank you!Questions? Discussion?

  28. If you want to read more about Epigenetics… • Chapter 10 of T.A. Brown’s Genomes (3/E), entitled “Accessing the Genome” is an good place to start • Special issue of Science 10 Aug. 2001 has a bunch of excellent articles written by pioneers in the field. (slightly dated, but still relevant) • Science Functional Genomics Resources: Epigenetics (portal hosted by the Americal journal, Science) – gives a series of articles published in the field, and also a list of useful websites http://www.sciencemag.org/feature/plus/sfg/resources/res_epigenetics.dtl

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