Transcript Epigenetics
Gregor Mendel (1823-1884) DNA (gene) Transcription RNA processing (splicing etc) mRNA Translation Folding Post translational modifications Protein Proteolysis Peptides/amino acids William Bateson (1861-1926) coined the name “genetics” in 1909 Genetics is the study of genes Whether geneticists study at the molecular, cellular, organismal, familial, population, or evolutionary level, genes are always central to their studies. Topics studied in the department of Genetics • • • • • • • • • • • • • Telomeres of chromosomes Cell cycle Nuclear architecture Population genetics Genetics of tomatoes Quantitative traits of milk production in cows Chromosome X inactivation RNA splicing Yeast meiosis Genetics of the CF disease Chromosomal fragile sites Human stem cells Oncogenes Transcription QuickTime™ and a Animation decompressor are needed to see this picture. Translation QuickTime™ and a Animation decompressor are needed to see this picture. Promoters Promoters, enhancers, silencers etc. Alternative splicing- gives rise to different proteins from the same gene How many genes do we have ? How many genes do we have ? The answer to this question is almost meaningless because: How many genes do we have ? The answer to this question is almost meaningless because: • Each gene can give rise to several proteins by alternative splicing How many genes do we have ? The answer to this question is almost meaningless because: • Each gene can give rise to several proteins by alternative splicing • And each protein can be modified in multiple ways by phosphorylation, methylation, acetylation, glycosylation etc. How many genes do we have ? The answer to this question is almost meaningless because: • Each gene can give rise to several proteins by alternative splicing • And each protein can be modified in multiple ways by phosphorylation, methylation, acetylation, glycosylation etc. • These modified proteins can further take part in different protein complexes. All the cells in the organism have the same DNA • DNA is packed together with histones and other proteins into chromatin. • Chromatin is a highly dynamic material which carries a substantial amount of epigentic information. • All cells in the organism carry the same genetic material, however each cell type expresses different genes. Epigenetics • Epigenetics - Heritable changes in gene expression that operate outside of changes in DNA itself Chromatin remodeling • Protein expression can be induced and repressed over many orders of magnitude. An important part of this regulation is exerted via chromatin remodeling by DNA methylation and numerous modifications mainly of the N-termini of histones acetylation, methylation, phosphorylation and ubiquitilation. Epigenetic chromatin regulation A. Modification at the DNA level 1. cytosine methylation B. Histone modification - the histone code 1. Histone acetylation 2. Histone methylation 3. Histone phosphorylation 4. Histone ubiquitilation 5. Different types of histones The five nucleotides that make up the DNA Mutations at 5’ methyl cytosine cannot be identified and repaired CpG dinocleotides are palindromic 5’ CpG 3’ 3’ GpC 5’ CpG dinocleotides are palindromic 5’ CpG 3’ 3’ GpC 5’ Maintenance of methylation Brand eis, M., Ariel, M. & Cedar, H. ( 1 99 3 ) Bioessays 1 5 , 70 9-71 3. Methylation is globally erased during gametogenesis and embryogenesis Kafri, T., Ariel, M., Brand eis, M., Sh emer, R., U rven, L., McCarrey, J., Cedar, H. & Razi n, A. (199 2) Genes Dev 6, 705-714. DNA demethylation of early embryos 3h 6h 8h Aphidicolin First met. P P P M M M P M 22h 2 cells Mayer, W., N iveleau, A., W alt er, J., Fund ele, R. & Haaf , T. ( 20 00) Natu re 40 3, 501-2 45h 4 cells Establishment of DNA methylation pattern • The methylation pattern of the genome is established anew every generation. In that sense methylation is an epigentic phenomenon - it influences the genetic material but it is not inherited from one generation to another. • All methylation (or at least almost all) is erased during early embryogenesis and reestablished Genomic imprinting Some genes are expressed only from the maternal genome and some only from the paternal genome Genomic imprinting Some genes are expressed only from the maternal genome and some only from the paternal genome It is estimated that about 40 genes are imprinted and they can be found on several different chromosomes Genomic imprinting Some genes are expressed only from the maternal genome and some only from the paternal genome It is estimated that about 40 genes are imprinted and they can be found on several different chromosomes For example - igf2, h19, igf2r and genes involved in the Angelman and Prader Willi syndromes Control (P+M) Maternal Paternal Imprinting is maintained by DNA methylation Roles of DNA methylation • • • • • Transcriptional silencing Protecting the genome from transposition Genomic imprinting X inactivation Tissue specific gene expression Epigenetic chromatin regulation A. Modification at the DNA level 1. cytosine methylation B. Histone modification - the histone code 1. Histone acetylation 2. Histone methylation 3. Histone phosphorylation 4. Histone ubiquitilation 5. Different types of histones Role of histone acetylation • Acetylated histones open up the chromatin and enable transcription. Histones are acetylated by HAT (histone acetylases) which are parts of many chromatin remodeling and transcription complexes. Role of histone de-acetylation • Deacetylated histones are tightly packed and less accessible to transcription factors. • Histones are deacetylated by HDAC (histone de-acetylase) proteins. Histone phosphorylation (H3) 1. Histones are phosphorylated during mitosis. 2. Histones are also phosphorylated by signal transduction pathways like the ERK pathway in response to external signals. It is not known how (and if) this phosphorylation contributes to gene expression. Epigenetic chromatin regulation A. Modification at the DNA level 1. cytosine methylation B. Histone modification - the histone code 1. Histone acetylation 2. Histone methylation 3. Histone phosphorylation 4. Histone ubiquitilation 5. Different types of histones QuickTime™ and a None decompressor are needed to see this picture. Epigenetic chromatin regulation A. Modification at the DNA level 1. cytosine methylation B. Histone modification - the histone code 1. Histone acetylation 2. Histone methylation 3. Histone phosphorylation 4. Histone ubiquitilation 5. Different types of histones