Differential gene expression:enhancersOur eye and muscle cells are differentbecause:A. They carry different sets of genesB. They transcribe different sets of genesC. They synthesize different sets of proteinsD. They synthesize identical sets of proteins, butuse them in different waysThe Paradigm of Differential GeneActivityThe cells that descend from the zygotehave different forms and functionsbecause of differential utilization of thesame genetic informationEnhancerAn enhancer is a DNA sequence that controlsefficiency and rate of transcription of a gene. Inother words, enhancers tell when and where agene promoter can be used and how much of thegene product to make.Enhancers are modularMany genes are expressed in more than onesubset of cells or tissues. Such genes will usuallyhave several enhancers, each of which will beresponsible for turning the transcription on in adifferent set of cells.Mouse Pax-6 geneTranscriptional enhancers are modular!-galactosidaseExpression ofreporter genedriven by eyeenhancer (B)How do enhancers work?Enhancers contain binding sites for transcriptionfactors: activators or repressors of transcription.Enhancers are combinatorial: more than onetranscription factor needs to bind in order toregulate gene expressionCombinatorial action of transcription factorsdetermines the tissue specificity of gene expressionChick !1 lens crystallin gene (eye)Rat somatostatin gene (pancreas)Group activity: what are theexpression patterns of genesE, F and G?FA or CGA or CB and DFBAERepressed byActivated byGeneThe enhancers of genes E, F and G are regulated in the following way:How do transcription factorswork?• Bind DNA sequence-specifically--DNA-binding domain• Increase (activator) or decrease (repressor)frequency of transcription of gene--Co-activator or co-repressor recruitmentdomain• Some form dimeric or other complexes withother DNA-binding proteins--Dimerization/ protein-proteininteraction domainMicrophtalmia (Waardenburgsyndrome type 2)Heterozygous condition characterized by deafness, smalleyes with multicolored irises, and a white forelock. Caused bymutations in human MITF gene.Fig. 5.8 Three-dimensional model of thehomodimeric transcription factor MITF (one proteinshown in red, the other in blue) binding to apromoter element in DNA (white)MITF core bindingsite:CATGTGTranscription factors: anothermechanism of actionTake home messages:Enhancers:Enhancers are modular. Example: P ax6 expression in theeye, pancreas and brain is regulated by differentenhancers of P ax6 gene.Within these modules, combinatorial input of transcriptionfactors is required. Example: in order to activate the chickcrystallin gene, Pax6 and Sox2 transcription factors needto be present in the nucleus and bind the enhancer.Take home messages:Transcription factors• Contain a DNA binding domain, an activation orrepression domain (or both) and, sometimes, aprotein-protein interaction domain (a dimerizationdomain, for example)• Act through:1. Recruitment of chromatin-remodeling enzymes(histone acetyl-transferases, histone deacetylases)or2. Interactions with basal transcription factors involvedin binding RNA polymerase to the promoter (