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Berkeley MCELLBI 140 - Lecture Notes

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E. coli = E. lephant ?Analogy and homology as tools in genetic investigationSlide 3a cells produce a pheromone and a receptor a cells produce a pheromone and a receptor diploid (a/a) cells produce none of the aboveSlide 5Slide 6The phenotype of a haploid yeast cell with respect to mating is determined by transcription factorsSlide 8Amazing but trueSlide 10Slide 11Slide 12Slide 13Screen for silencing mutantsThe mating pheromone responseHow to screen for silencing mutantsSlide 17Slide 18The dataQuestionHomeworkHow can one explain the evolution of two distinct mating types in budding yeast?Two mating types have evolved under selective pressure to avoid inbreedingGranddaughters of any given mother can switch mating typeSlide [email protected] 27Epigenetic inheritanceCompaction into chromatin brings the eukaryotic genome to life“Beads on a string”Slide 31Histones: Conserved and ChargedSlide 33“Extremely conserved histone H4 N terminus is dispensable for growth but essential for repressing the silent mating loci in yeast” (M. Grunstein)Slide 35Slide 36Slide 37“Genetic evidence for an interaction between SIR3 and histone H4 in the repression of the silent mating loci in Saccharomyces cerevisiae”Slide 39Slide 40And 5 years later …Houston, we have a …The silencersThe key questionRoy Frye (Pitt)J. Denu: Sir2p is a NAD-dependent histone deacetylase (HDAC)Slide 47Slide 48Next time: the genetics of heterochromatin in metazoa1MCB 140 11/27/06E. coli = E. lephant ?F. JacobJ. MonodA. PardeeD. HawthorneH. DouglasY. Oshima1965 19662MCB 140 11/27/06Analogy and homology as tools in genetic investigationAnimalMandibular Arch (ventral)Mandibular Arch (dorsal)Hyoid Arch(dorsal)Shark Meckel's cartilagePalatoquadrate cartilageHyomandibular cartiliageAmphibian Articular (bone) Quadrate (bone) StapesMammal Malleus Incus Stapes3MCB 140 11/27/064MCB 140 11/27/06a cells produce a pheromone and  receptor cells produce  pheromone and a receptordiploid (a/) cells produce none of the above5MCB 140 11/27/06ShmooAl Capp (1948) – Li’l Abner6MCB 140 11/27/06Marsh and Rose diagram7MCB 140 11/27/06The phenotype of a haploid yeast cell with respect to mating is determined by transcription factorsAn  cell produces two transcription factors, Mat1p and Mat2p, that ensure expression of  specific genes, including the pheromone and receptor, and repress expression of a specific genes.In an a cell, Mat1p and Mat2p are not expressed, and a different transcription factor is expressed, Mata1p. The  genes are off, and the a genes (pheromone and receptor) are on.8MCB 140 11/27/06A.99MCB 140 11/27/06Amazing but trueA wild-type haploid yeast cell contains THREE copies of mating type-determining genes:•Copy #1: the  1 and 2 genes (silent).•Copy #2: the a1 and a2 genes (also silent).•Copy #3: An additional copy of genes in item 1, or of the genes in item 2, but active.Whichever genes are contained in copy #3 determines the mating type.10MCB 140 11/27/06A.11A.1211MCB 140 11/27/06“An easily understood, workable falsehood is more useful than an incomprehensible truth.”12MCB 140 11/27/06cenMATHMLHMRaa1a2 cellactive silentsilent13MCB 140 11/27/06Loss of silencing at the silent mating type cassettes creates a “nonmater” – a haploid that is a/ and that thinks it’s a diploid.cenMATHMLHMRaa1a2 cellactive activeactive14MCB 140 11/27/06Screen for silencing mutantsA sample “screen”:1. Take haploid cells.2. Mutate them.3. Screen for those that don’t mate.Problem: mating is so much more than proper silencing of mating type loci!!15MCB 140 11/27/06The mating pheromone responseJeremy ThornerThorner diagramAlso see Fig. A.13.16MCB 140 11/27/06How to screen for silencing mutantscenMATHMLHMRaa1a2a cella1a2active silentsilentJasper Rine and Ira Herskowitz (1987) Genetics 116: 9-22.17MCB 140 11/27/06How to screen for silencing mutantscenmata1-1HML a1a2active silentsilentJasper Rine and Ira Herskowitz (1987) Genetics 116: 9-22.HMLNote: mata1-1 is a special allele of the a gene – it is recessive to 18MCB 140 11/27/06Jasper Rine and Ira Herskowitz (1987) Genetics 116: 9-22.Rine schematicmate to a cells19MCB 140 11/27/06The data•Colonies screened: 675,000•Colonies that mated to a: 295•Major complementation groups: 4silent information regulators:SIR1, SIR2, SIR3, SIR4Jasper Rine and Ira Herskowitz (1987) Genetics 116: 9-22.20MCB 140 11/27/06QuestionWhat molecular mechanisms are responsible for silencing at the mating type loci?  heterochromatin formation in metazoaprostate cancer breast cancer ageing “normal” gene regulation in mammals21MCB 140 11/27/06Homework22MCB 140 11/27/06How can one explain the evolution of two distinct mating types in budding yeast?Surely a pathway could have just evolved for the fusion of two identical haploid cells?23MCB 140 11/27/06Two mating types have evolved under selective pressure to avoid inbreedingMD1D2D1D2One evolutionary advantage of mating is the production of novel genotypic combinations via the fusion of two genomes with different life histories.x24MCB 140 11/27/06Granddaughters of any given mother can switch mating type25MCB 140 11/27/0626MCB 140 11/27/[email protected] 140 11/27/06cenMATHMLHMRaa1a2 cellcenMATHMLHMRaa1a2a cella1a2active silentsilent28MCB 140 11/27/06Epigenetic inheritance•In an  strain, the genetic information at MAT and at HML is identical.•The one at MAT is expressed, but the one at HML is not – it is epigenetically silenced.Epigenetic: mitotically stable (persists through cell division) change in gene expression state that is not associated with a change in DNA sequence.Examples: X chromosome inactivation; imprinted genes; transgene silencing in gene therapy.29MCB 140 11/27/06> 1 metre< 10-5 metres15,000x compactionCompaction into chromatin brings the eukaryotic genome to life30MCB 140 11/27/06“Beads on a string”31MCB 140 11/27/06The Nucleosome Core Particle:8 histones, 146 bp of DNA32MCB 140 11/27/06Histones: Conserved and ChargedH.s. = Lycopersicon esculentum33MCB 140 11/27/0634MCB 140 11/27/06“Extremely conserved histone H4 N terminus is dispensable for growth but essential for repressing the silent mating loci in yeast” (M. Grunstein) Kayne et al. (1988) Cell 55: 27-39.Fig. 3 kayne35MCB 140


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Berkeley MCELLBI 140 - Lecture Notes

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