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Gene Regulation

Gene Regulation. Organisms have lots of genetic information, but they don’t necessarily want to use all of it (or use it fully) at one particular time. Eukaryotes: Development, differentiation, and homeostasis In going from zygote to fetus, e.g., many genes are used that are then turned off.

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Gene Regulation

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  1. Gene Regulation • Organisms have lots of genetic information, but they don’t necessarily want to use all of it (or use it fully) at one particular time. • Eukaryotes: Development, differentiation, and homeostasis • In going from zygote to fetus, e.g., many genes are used that are then turned off. • Liver cells, brain cells, use only certain genes • Cells respond to internal, external signals

  2. Gene regulation continued • Prokaryotes: respond rapidly to environment • Transcription and translation are expensive • Each nucleotide = 2 ATP in transcription • Several GTP/ATP per amino acid in translation • If protein is not needed, don’t waste energy! • Changes in food availability, environmental conditions lead to differential gene expression • Degradation genes turned on to use C source • Bacteria respond to surfaces, new flagella etc. • Quorum sensing: sufficient # of individuals turns on genes.

  3. On/off, up/down, together • Sometimes genes are off completely and never transcribed again; some are just turned up or down • Eukaryotic genes typically turned up and down a little compared to huge increases for prokaryotes. • Genes that are “on” all the time = Constitutive • Many genes can be regulated “coordinately” • Eukaryotes: genes may be scattered about, turned up or down by competing signals. • Prokaryotes: genes often grouped in operons, several genes transcribed together in 1 mRNA.

  4. How is gene expression controlled? • Transcription: most common step in control. • RNA processing: only in eukaryotes. • Alternate splicing changes type/amount of protein. • Translation: prokaryotes, stops transcrp. early. • Stability of mRNA: longer lived, more product. • Post-translational: change protein after it’s made. Process precursor or add PO4 group. • DNA rearrangements. Genes change position relative to promoters, or exons shuffled.

  5. Gene regulation in Prokaryotes • Bacteria were models for working out the basic mechanisms, but eukaryotes are different. • Some genes are constitutive, others go from extremely low expression (“off”) to high expression when “turned on”. • Many genes are coordinately regulated. • Operon: consecutive genes regulated, transcribed together; polycistronic mRNA. • Regulon: genes scattered, but regulated together.

  6. Rationale for Operon • Many metabolic pathways require several enzymes working together. • In bacteria, transcription of a group of genes is turned on simultaneously, a single mRNA is made, so all the enzymes needed can be produced at once. http://galactosaemia.com.hosting.domaindirect.com/images/metabolic-pathway.gif

  7. Proteins change shape When a small molecule binds to the protein, it changes shape. If this is a DNA-binding protein, the new shape may cause it to attach better to the DNA, or “fall off” the DNA. http://omega.dawsoncollege.qc.ca/ray/genereg/operon3.JPG

  8. Definitions concerning operon regulation • Control can be Positive or Negative • Positive control means a protein binds to the DNA which increases transcription. • Negative control means a protein binds to the DNA which decreases transcription. • Induction • Process in which genes normally off get turned on. • Usually associated with catabolic genes. • Repression • Genes normally on get turned off. • Usually associated with anabolic genes.

  9. Structure of an Operon • Structural genes: actual genes being regulated. • Promoter region: site for RNA polymerase to bind, begin transcription. • Operator region: site where regulatory protein binds. • Regulatory protein gene: need not be in the same area as the operon. Protein binds to DNA. www.cat.cc.md.us

  10. Animations • Look up Animations showing the effects of the lactose repressor on the lac operon. • As with translation, details will vary. For example, the lactose repressor protein is a tetramer. How many sites depict it this way? • Be wary of oversimplification.

  11. The Lactose Operon • The model system for prokaryotic gene regulation, worked out by Jacob and Monod, France, 1960. • The setting: E. coli has the genes for using lactose (milk sugar), but seldom sees it. Genes are OFF. • Repressor protein (product of lac I gene) is bound to the operator, preventing transcription by RNA polymerase. Green: repressor protein Purple: RNA polymerase

  12. Lactose operon-2 • When lactose does appear, E. coli wants to use it. Lactose binds to repressor, causing shape change; repressor falls off DNA, allows unhindered transcription by RNA polymerase. Translation of mRNA results in enzymes needed to use lactose.

  13. Lactose operon definitions • Control is Negative • When repressor protein is bound to the DNA, transcription is shut off. • This operon is inducible • Lactose is normally not available as a carbon source; genes are “shut off” • In bacteria, many similar operons exist for using other organic molecules. • Proteins for transporting the sugar, breaking it down are produced.

  14. Repressible operons • Operon codes for enzymes that make a needed amino acid (for example); genes are “on”. • Repressor protein is NOT attached to DNA • Transcription of genes for enzymes needed to make amino acid is occurring. • The change: amino acid is now available in the culture medium. Enzymes normally needed for making it are no longer needed. • Amino acid, now abundant in cell, binds to repressor protein which changes shape, causing it to BIND to operator region of DNA. Transcription is stopped. • This is also Negative regulation (protein + DNA = off).

  15. Repression picture Transcription by RNA polymerase prevented.

  16. Regulation can be fine tuned The more of the amino acid present in the cell, the more repressor-amino acid complex is formed; the more likely that transcription will be prevented.

  17. Positive regulation • Binding of a regulatory protein to the DNA increases (turns on) transcription. • More common in eukaryotes. • Prokaryotic example: the CAP-cAMP system • Catabolite-activating Protein • cAMP: ATP derivative, acts as signal molecule • When CAP binds to cAMP, creates a complex that binds to DNA, turning ON transcription. • Whether there is enough cAMP in the cell to combine with CAP depends on glucose conc.

  18. Positive regulation-2 • Glucose is preferred nutrient source • Other sugars (lactose, etc.) are not. • Glucose inhibits activity of adenylate cyclase, the enzyme that makes cAMP from ATP. • When glucose is high, cAMP is low, less cAMP is available to bind to CAP. • CAP is “free”, doesn’t bind to DNA, genes not on. • When glucose is low, cAMP is high • Lots of cAMP, so CAP-cAMP forms, genes on. • Works in conjunction with induction.

  19. Cartoon of Positive Regulation

  20. Attenuation: fine tuning repression • Attenuation occurs in prokaryotic repressible operons. Happens when transcription is on. • Regulation at the level of translation • Several things important: • Depends on base-pairing between complementary sequences of mRNA • Requires simultaneous transcription/translation • Involves delays in progression of ribosomes on mRNA

  21. Mechanism of attenuation- tryp operon

  22. Mech. of attenuation -2

  23. Attenuation-3

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