11MCB 140, 9-26-082MCB 140, 9-26-08Gene Æ phenotypeOther genes Æ epistasis Æ variable expressivity (sickle-cell anemia)The environment Æ “norm of reaction” Ævariable penetrance (BRCA1-induced breast cancer)Epigenetic effects3MCB 140, 9-26-08EpigeneticsMitotically and/or meiotically resistant inheritance of a phenotypic difference that occurs without a change in the DNA sequence.4MCB 140, 9-26-08Maize (corn) – Zea mays5MCB 140, 9-26-08Courtesy of Prof. Jay Hollick, MCB Department6MCB 140, 9-26-08?!!!R. Alexander Brink, 1950Vicky Chandler, Jay Hollick27MCB 140, 9-26-08What is going onThis 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.8MCB 140, 9-26-08A critical aspect of the paramutation process – one that is shared by many epigenetic processesIt 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).9MCB 140, 9-26-08Genetics 140 1379-138710MCB 140, 9-26-0832C LL 22C LLGrandpaternal seedling conditionsGenetics 140 1379-138711MCB 140, 9-26-08An evolutionary perspectiveMikula (1995) Genetics 140 1379-138712MCB 140, 9-26-08Persephone, the Greek goddess of Spring313MCB 140, 9-26-08A 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)14MCB 140, 9-26-08VernalizationA) 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 vernalization-requiring habit. All plants were grown in long days (inductive photoperiods) without vernalization. The rapid-flowering 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)15MCB 140, 9-26-08“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)16MCB 140, 9-26-08R. Amasino The Plant Cell 16:2553-2559 (2004)“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.”17MCB 140, 9-26-08From screen … To mechanism:Hollick and Chandler Alleman et al.Genetics, Vol. 157, 369-378 Nature 442, 295-298 18MCB 140, 9-26-08Arabidopsis thaliana419MCB 140, 9-26-08Some mutations that affect flower structure20MCB 140, 9-26-08S. Jacobsen and E. Meyerowitz“Superman”Wild-type flower: 6 stamens (♂).superman null mutations: 12 stamens.21MCB 140, 9-26-08S. Jacobsen, UCLA22MCB 140, 9-26-08No comment on the nomenclatureThere 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, UCLA23MCB 140, 9-26-085’-CG-3’3’-GC-5’24MCB 140, 9-26-08Normal CellCancer Cellhypermethylationof CpG Island= SILENCINGhypomethylationof Gene Body and Bulk Chromatin11 2 32 3?Jones and Baylin Nat Rev Genet. 2002 Jun;3(6):415-28525MCB 140, 9-26-08S. Jacobsen, UCLA26MCB 140, 9-26-08Suppressor mutants:Cmt3 (the DNMT)or kyp (kryptonite)clk-stS. Jacobsen, UCLASuppressors of clark kent27MCB 140, 9-26-08kyp (kryptonite) codes for an H3K9 histone methyltransferase!Jackson et al. (Jacobsen) Nature 416: 556-560 (2002).28MCB 140, 9-26-0829MCB 140, 9-26-08Histone methylation30MCB 140, 9-26-082007:Young, Jaenisch –Nature, CellBernstein – CellWade – New York Times631MCB 140, 9-26-08The 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.32MCB 140, 9-26-08Rusche L, Kirchmaier A, Rine J (2002) Mol. Biol. Cell 13: 2207.Resveratrol33MCB 140, 9-26-08Gene Inactivation Associated With CpG Island Methylation In CancerGene Locus Function Cancer• Rb• VHL• P16• P15• E-cadherin• Estrogen Rec• GST-π• O6MGMT• Calcitonin13q14.23p259p219p2116q22.16q2511q1310q24-qter11p15Cell cycle regulationRNA elongationCDK inhibitorCDK inhibitor,
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