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1、Transcriptional RegulationThe regulation of transcription is one of the most important ways in which genes are regulated.Prokaryotes and Eukaryotes DiffernucleosomeProkaryotes and Eukaryotes DifferThere is a fundamentally different logic of gene regulation in bacteria and eukaryotes.In bacteria,ther
2、e is a active ground state and genes are often regulated by repressionProkaryotes and Eukaryotes DifferWhile eukaryotes have an inactive ground state and genes are typically regulated by activation.Allosteric RegulationSmall molecule effectors(效效应应物物)can alter the activity of transcription factors.T
3、he lac OperonThe lac operon was one of the first genetic regulatory systems to be understood in detail.The lac operon is responsible for lactose utilization,and it is only active when lactose(or related galactosides)are present.Lactose and b-Galactosidease半乳糖葡萄糖 b b-GalactosideaseLac Z gene product乳
4、糖-半乳糖苷酶透性酶半乳糖苷转乙酰酶异丙基-D-硫代半乳糖苷 甘油甘油 葡萄糖葡萄糖 Mutations in the lac OperatorlacOc mutants have an altered sequence that does not allow the repressor to bind.This results in a cis-acting constitutive phenotype.Mutations in the lac RepressorIn contrast,lacI mutants,which lack repressor activity,can be com
5、plemented in merozygotes.Thus,lacI mutants are trans-acting.Mutations in the lac RepressorlacIs mutants,in which the repressor cannot bind to the inducer,are uninducible mutants.These lacI mutants are also trans-acting.The Core PromoterThe core promoter sequences we saw in our previous discussion of
6、 prokaryotic transcription can be shown to have an impact on transcriptional activity.Glucose RepressionThe lac operon is also regulated by glucose repression-it is only active when lactose is present and glucose is absent.This is because glucose is a preferred carbon source.Glucose regulation is in
7、direct,since it involves the second messenger cAMP(cyclic AMP).The cAMP signal tells the cell that glucose is absent.降解物激活蛋白降解物激活蛋白CAP Protein Bends DNAWhen the CAP-cAMP complex binds DNA it causes the DNA to bend.This bending appears to be the cause of the transcriptional activation by the CAP-cAMP
8、 complex.The trp OperonThe trp operon is responsible for tryptophan biosynthesis.When would we expect to see trp operon activity?分支酸邻胺苯甲酸 磷酸核糖 吲哚 The trp OperonThe trp operon is active when tryptophan is absent.Tryptophan acts as a small molecule co-repressor,binding the trp repressor and causing th
9、e trp repressor to bind DNA in the bound state.The trp OperonThe trp operon is also regulated by attenuation.Attenuation is an interaction between transcription and translation.There is a short open reading frame(ORF)upstream of the trp genes.This ORF has two Trp codons.If a ribosome stalls on these
10、 codons,transcription continues.Otherwise,it is terminated.Eukaryotic PromotersEukaryotic promoters are much more complex and the elements present are much more variable.The TATA box is one of the most important,and the majority of promoters have it.The CCAAT and GC boxes are present in many promote
11、rs,but their presence is more variable.Eukaryotic PromotersThese boxes can also be defined mutationally.More recently,computation has been used to define them.EnhancersEnhancers are regulatory sites that can be quite far away in terms of the sequence.The EnhanceosomeReporter GenesA reporter gene lik
12、e-galactosidase can be used to study different enhancer elements.Here,Drosophila embryos stained for-gal activity are shown regulated by dpp enhancer elements are shown.Lateral Ectoderm(LE)Imaginal Disc(ID)Chromatin and TranscriptionThe compaction of eukaryotic DNA into chromatin has a profound impa
13、ct on transcriptional regulation.Dosage CompensationFemale mammals are mosaics,with one of their two X chromosomes inactivated.Inactivation involves the transcription of a non-coding gene called XIST.Other organisms have other means of dosage compensation,such as hypertranscription of the male X-lin
14、ked genes(Drosophila)or reducing X-linked transcription(C.elegans hermaphrodites).Prader-Willi&Angelman SyndromesBoth of these genetic disorders are caused by deletion of a segment of chromosome 15.However,the syndromes differ:Prader-Willi Syndrome-obesity,mental retardation,short stature.Angelman S
15、yndrome-uncontrollable laughter,jerky抽筋的 movements,and other motor and mental symptoms.The syndrome that develops depends upon the parent that provided the mutant chromosome.PWSASPWSMousemodelASMousemodelFrom Annu Rev Genomics&Hum GenetPrader-Willi&Angelman SyndromesPrader-Willi Syndrome-develops wh
16、en the abnormal copy of chromosome 15 is inherited from the father.Angelman Syndrome-develops when the abnormal copy of chromosome 15 is inherited from the mother.The differences reflect the fact that some loci are imprinted-so only the allele inherited from one parent is expressed.The chromosome 15
17、 region contains genes with both maternal and paternal imprinting.ImprintingImprinting is another type of epigenetic regulation(表观遗传调控),in which the parent that donates an allele determines whether it is active.The silenced allele has specific changes in DNA methylation that are established in the p
18、arents germline.Chromatin RemodelingYeast mutants that cannot change mating type or ferment sucrose蔗 糖(swi and snf mutants)were identifiedMany factors specific to mating type switching or the regulation of invertase were identified,but one very general transcription factor(SWI-SNF)was identified.Thi
19、s factor moves nucleosomes away from the TATA box of genes.Perturbing Histone LevelsChanging the amounts of histone H4 can alter gene expression globally.If we complement a histone H4 mutant with a plasmid that has H4 under GAL gene control it is possible to deplete histones by shifting the cells to
20、 glucose medium.Histone depletion activates genes that are inducible.Histone ModificationJust as DNA can be modified by methylation,histones can be modified by methylation and acetylation.Acetylation is better studied,and it is correlated with gene activation.Some transcription factors,like GCN5,are
21、 histone acetyltransferases.Repressors,like RPD3,are histone deacetylasesThe EnhanceosomeThe enhanceosome will act to recruit histone acetyltransferase activity,which results in the recruiting SWI-SNF(moving nucleosomes)and ultimately TATA-binding protein(TBP)and RNA pol II.The Histone CodeThe histone code can be“inherited”by modifying newly synthesized nucleosomes after DNA replication.This represents an example of epigenetic inheritance.