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Gene Regulation Why do genes need to be “regulated” or controlled? -Cells don’t always need all of their genetic information to be active all of the time. For example: 1. In prokaryotes genes are regulated so the cells don’t waste energy making proteins that aren’t required all of the time 2. In multicellular (eukaryotic) organisms each type of cell carries out specific activities which require only a distinct set of proteins, not all of the proteins in the entire genome. • These cells all contain the same DNA, the difference is caused by regulating gene expression so that only the required genetic information gets expressed in a cell at any given time. (cell differentiation) • Expressing a gene involves 3 main steps – Transcription of DNA to RNA – Translation of RNA to a polypeptide chain – Activation of a protein • So, the expression of a gene can be regulated at several different times using several different mechanisms • Types of Control Mechanisms – Regulatory proteins • Negative control – slow down or stop gene activity • Positive control – promote or enhance gene activity – Non-coding DNA sequences • Promoters – signal the start of a gene • Enhancers – binding sites for some activator proteins – Chemical modifications • Methylation – adding CH3 to nucleotide bases causes them to shut down or inactivate a gene • Demethylation – removing CH3 can cause a gene to activate • Acetylation – attaching acetyl group (CH3CO) to histones (proteins that DNA wraps around) make it loosen its grip on its associated DNA so it can be transcribed • These control mechanisms respond to various signals • Some signals originate inside the cell (intracellular) while others are from the cell environment (extracellular) – Examples – hormones and the absence or presence of a certain chemical • In prokaryotes: – Some genes are constantly transcribed because their proteins are always needed (constitutive genes) – Other genes are only transcribed when their proteins are required – Example: Bacteria growing in the colon of an adult cow do not have lactose (milk sugar) available as an energy source, but if they were in the colon of a calf they would. So, should all of those bacteria take the time and energy to produce the enzymes (proteins) that digest lactose all of the time. No, only when the environment requires it. – Most prokaryotic controls are transcriptional controls • In bacteria, functionally related genes are regulated together in gene “complexes” • This gene “complex” is called an operon • An operon is several genes involved in the same process and they function as a single unit • Operons were discovered by French microbiologists Francis Jacob & Jacques Monod • Operons are composed of several parts – Regulator gene – codes for repressor protein – Promoters – sequence of DNA where RNA polymerase binds to start transcription – Operators – site where repressor proteins may bind (“on/off” switch) – Structural genes (several) – code for the proteins • When a repressor protein binds to the operator, transcription of the structural genes is inhibited. The Lac Operon • An inducible operon or an example of a positive control mechanism • The operon will not be transcribed unless an inducer inactivates its repressor • Its repressor is normally active, therefore the operon is usually “turned off” • It consists of 3 structural genes that code for 3 enzymes that breakdown lactose (lac z, lac y, & lac a) - see book • If lactose is absent: – The lac-operon is “off” and the genes are not transcribed, this is its usual state – The repressor protein is bound to the operator(s) and blocks the RNA polymerase – it is referred to as inducible because it can be turned on • If lactose is present: – The operon is turned “on” by the removal of the repressor – An inducer (allolactose) binds to the repressor and inactivates it so that it no longer blocks the RNA polymerase – The operon can then be transcribed and the enzymes that break down lactose can be produced Show CD-ROM animation!! The trp Operon • A repressible operon or an example of a negative control mechanism is usually on but can be turned off. • The operon will be transcribed unless a corepressor activates its repressor • Its repressor is normally inactive, therefore the operon is usually “turned on” • It consists of 5 structural genes that code for enzymes the cell needs to synthesize the amino acid tryptophan • When trytophan levels are low, the repressor protein is inactive and not bound to the operon – The RNA polymerase can bind and transcribe the operon – This is the “normal” state • When tryptophan levels are high, tryptophan (itself) binds to the repressor to activate it – Tryptophan acts as a co-repressor – The repressor is then able to bind to the operon, blocking RNA polymerase and stopping transcription Eukaryotic Controls in General • Have 4 levels of control – Transcriptional – if a gene is not transcribed, there is no gene product – Post-transcriptional – processing of RNA and speed it leaves nucleus – Translational – life expectancy of mRNA – Post-translational – activating or modifying the polypeptide chain to make an active protein or enzyme Specific Eukaryotic Controls • Transcriptional Controls – Organization of chromatin • Euchromatin –relaxed form, genetically active • Heterochromatin – denser form, genetically inactive – Ex. Mammalian females have 2- X chromosomes, one of the X chromosomes is inactive in the cells (we call these Barr bodies), it is inactivated by chance – Telomeres – ends of chromosomes • Non-coding portions – Introns – Tandom repeats – Regulatory proteins • Transcription factors and enhancers help RNA polymerase bind to the promoter so transcription can occur Post-transcriptional Control • Begins once there is an mRNA transcript • Processing before mRNA leaves nucleus – Differential excision of introns and splicing of exons – Affects the final protein product • Also, the speed at which mRNA leaves the nucleus affects how much product can be made Translational Control • Begins when the mRNA reaches the cytoplasm • “Masking” of mRNA – just because mRNA is in the cytoplasm doesn’t mean it gets translated • Life Expectancy of mRNA – the longer the mRNA is active and in the cytoplasm, the product can be made • Influence of Hormones – hormones can stabilize RNA and extend their life expectancy (ex. Prolactin and casein) Post-translational Control • Begins after polypeptide is made • Activation of protein product – some proteins are not active after synthesis, they need to be modified (have stuff added or removed) • Degradation of a protein – many proteins are short-lived in cells and are degraded so they are no longer active