MCB 140 9 26 08 1 Gene phenotype Other genes epistasis variable expressivity sickle cell anemia The environment norm of reaction variable penetrance BRCA1 induced breast cancer Epigenetic effects MCB 140 9 26 08 2 Epigenetics Mitotically and or meiotically resistant inheritance of a phenotypic difference that occurs without a change in the DNA sequence MCB 140 9 26 08 3 Maize corn Zea mays MCB 140 9 26 08 4 Courtesy of Prof Jay Hollick MCB Department MCB 140 9 26 08 5 R Alexander Brink 1950 Vicky Chandler Jay Hollick MCB 140 9 26 08 6 What is going on This is paramutation a meiotically heritable change in the phenotype of a plant that results not from the physical alteration of the primary DNA sequence of the underlying genes but from an effect on their expression Recall Mendel s compromise that the two alleles of a gene reach in a heterozygous organism for the life of a plant In this case the compromise is not reached The Pl allele somehow causes the epigenetic silencing of the Pl allele silencing that persists through meiosis MCB 140 9 26 08 7 A critical aspect of the paramutation process one that is shared by many epigenetic processes It is sensitive to the environment paramutation can be variably expressive in other words the extent of paramutation can vary and how variable it is can be specified by the environment MCB 140 9 26 08 8 Genetics 140 1379 1387 MCB 140 9 26 08 9 Grandpaternal seedling conditions 32C LL Genetics 140 1379 1387 22C LL MCB 140 9 26 08 10 An evolutionary perspective Mikula 1995 Genetics 140 1379 1387 MCB 140 9 26 08 11 Persephone the Greek goddess of Spring MCB 140 9 26 08 12 A bit of plant biology the seeming paradox of vernalization Vernalization is the process by which prolonged exposure to cold temperatures promotes flowering Monocarpic species senesce after flowering and setting seed Plants that require vernalization to flower thus typically require two seasons to complete the life cycle and are usually classified as biennials or winter annuals Many winter annuals and biennials become established in the fall taking advantage of the cool and moist conditions optimal for their growth The vernalization requirement of such plants prevents flowering until spring has actually arrived R Amasino The Plant Cell 16 2553 2559 2004 MCB 140 9 26 08 13 Vernalization A A biennial cabbage Brassica oleracea variety with an obligate vernalization requirement that had been growing for five years without cold exposure The small plant in my daughter s hands is a summer annual variety of B oleracea that flowers rapidly without vernalization B and C Summer annual and vernalization requiring types of henbane B and Arabidopsis C In both examples a single dominant gene is responsible for the vernalizationrequiring habit All plants were grown in long days inductive photoperiods without vernalization The rapidflowering summer annuals which have initiated flowering are at left and the winter annual types at right R Amasino The Plant Cell 16 2553 2559 2004 MCB 140 9 26 08 14 I think it is reasonable to refer to the vernalization induced mitotically stable acquisition of the competence to flower as an epigenetic switch because it is a change that can be propagated through cell divisions in the absence of the inducing signal R Amasino The Plant Cell 16 2553 2559 2004 MCB 140 9 26 08 15 The vernalization mediated repression of FLC is epigenetic in the sense discussed above The repressed state of FLC is maintained after vernalized plants are returned to warm growing conditions Thus in Arabidopsis vernalization provides competence to flower by repressing the expression of a flowering repressor As expected FLC expression is on again in the next generation This resetting of the epigenetic switch during passage to the next generation is reminiscent of genomic imprinting in animals But the unique aspect of this switch is that the on to off direction of the switch is set by perception of the environment whereas the off to on direction is set by passage to the next generation R Amasino The Plant Cell 16 2553 2559 2004 MCB 140 9 26 08 16 From screen To mechanism Hollick and Chandler Genetics Vol 157 369 378 Alleman et al Nature 442 295 298 MCB 140 9 26 08 17 Arabidopsis thaliana MCB 140 9 26 08 18 Some mutations that affect flower structure MCB 140 9 26 08 19 S Jacobsen and E Meyerowitz Superman Wild type flower 6 stamens superman null mutations 12 stamens MCB 140 9 26 08 20 S Jacobsen UCLA MCB 140 9 26 08 21 No comment on the nomenclature There are two ways to mutate the SUPERMAN gene and get the same phenotype 12 stamens 1 Just delete the gene 2 Keep the gene as it and METHYLATE it The methylated form is an epi allele of SUPERMAN and is called clark kent S Jacobsen UCLA MCB 140 9 26 08 22 5 CG 3 3 GC 5 MCB 140 9 26 08 23 Normal Cell 1 2 3 2 3 Cancer Cell 1 hypermethylation of CpG Island SILENCING hypomethylation of Gene Body and Bulk Chromatin Jones and Baylin Nat Rev Genet 2002 Jun 3 6 415 28 MCB 140 9 26 08 24 S Jacobsen UCLA MCB 140 9 26 08 25 Suppressors of clark kent clk st S Jacobsen UCLA Suppressor mutants Cmt3 the DNMT or kyp kryptonite MCB 140 9 26 08 26 kyp kryptonite codes for an H3K9 histone methyltransferase Jackson et al Jacobsen Nature 416 556 560 2002 MCB 140 9 26 08 27 MCB 140 9 26 08 28 Histone methylation MCB 140 9 26 08 29 2007 Young Jaenisch Nature Cell Bernstein Cell Wade New York Times MCB 140 9 26 08 30 The molecular basis of epigenetic inheritance is the deposition and subsequent maintenance through mitosis plants and animals and meiosis plants of covalent marks such as methylation on the DNA and on the histones These marks do NOT change the DNA sequence but they change how the DNA sequence is read The machinery that deposits these marks the dys regulation of this machinery and how the marks are read out are without a doubt the 1 field of study in genetics today MCB 140 9 26 08 31 Resveratrol Rusche L Kirchmaier A Rine J 2002 Mol Biol Cell 13 2207 MCB 140 9 26 08 32 Gene Inactivation Associated With CpG Island Methylation In Cancer Gene Locus Function Cancer Rb 13q14 2 Cell cycle regulation Retinoblastoma VHL 3p25 RNA elongation Renal carcinoma P16 9p21 CDK inhibitor Carcinomas P15 9p21 CDK inhibitor TGF induced Leukemia glioma E cadherin 16q22 1 Invasion metastasis suppressor Breast prostate gastric Estrogen Rec 6q25 Hormone receptor Breast colon GST 11q13 Detoxifying enzyme Prostate O6MGMT 10q24 qter DNA repair Cell lines Calcitonin 11p15 Hormone Leukemia
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