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Regulation of Gene Expression

Regulation of Gene Expression. What are the “goals” of gene expression?. Prokaryotes: to respond to changes in the environment Eukaryotes: development Maintenance of different cell types Loss of control can be disastrous . Bacteria regulate transcription: operons.

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Regulation of Gene Expression

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  1. Regulation of Gene Expression

  2. What are the “goals” of gene expression? • Prokaryotes: to respond to changes in the environment • Eukaryotes: development • Maintenance of different cell types • Loss of control can be disastrous

  3. Bacteria regulate transcription: operons • Feedback inhibition by end product of pathway • Operon: expression of genes for enzymes

  4. What is an operon? A repressible operon

  5. Lac operon is inducible

  6. Repressible and inducible operons • Repressible • Repressor does not bind operator unless it interacts with co-repressor • Biosynthetic pathways • Inducible • Repressor is bound to operator unless molecule to be metabolized is present (inducer) • Catabolic pathways • When repressor is bound to operator, genes are not expressed (operon is turned off)

  7. Positive gene regulation Cell will use glucose preferentially cAMP accumulates when glucose is scarce

  8. Which genes are expressed when? • Unicellular organism • Environmental signals • Generally transcription is regulated • Multicellular organism • Development • Cell specialization • May change over time • More complicated!

  9. Gene expression in eukaryotic cell • Transcription is common control point • RNA processing • Stability of RNA • Protein modification

  10. Regulation of chromatin structure • Access to promoters enhanced by histoneacetylation • Histonemethylation and phosphorylation patterns • Methylation of DNA affects gene expression (along with histonedeacetylation) • Can be reversed

  11. Transcription of eukaryotic genes Many control elements

  12. What are the components of transcriptional regulation? • Transcription factors • Proximal activators • Distal control elements (enhancers) • DNA binding domain • Activation domains bind to other proteins • These are cell-specific • A few common structures, but found in different combinations in different cells

  13. Why is the same gene expressed in some cells but not others?

  14. What is the eukaryotic counterpart to an operon? • Co-expressed genes are usually not next to each other • Hormone-receptor complex can bind to control elements common to may genes

  15. Signal transduction pathways can activate many genes How many transcription factors are activated? Can the complex bind to more than one site on DNA?

  16. “Nuclear architecture” • Are chromosomes actually arranged in the nucleus?

  17. Post-transcriptional regulation • How much protein is made? • Can the protein be altered? • Can the transcript be modified in response to changes in the environment?

  18. Post-transcriptional regulation • Alternative PNA splicing • “selection” of exons • One gene can generate many forms of a protein • mRNA degradation • Some mRNAs are more stable (so can be translated more often) • 3’-UTR seems to be important

  19. Translation and beyond • 5’-cap and 3’-poly-A tail required for ribosome binding • Poly-A tail can be modified to allow binding • Regulatory proteins can bind to UTRs

  20. Post-translational modification • Many proteins require modification • Cleavage • Modification by phosphate groups, sugars, etc. • Signal peptides • Some proteins are supposed to be short-lived • Protein degradation is highly controlled

  21. mRNA, rRNA, tRNA…there’s more! • Not all DNA codes for protein • rRNA, tRNA (large nc (non-coding) RNAs) • Small RNAs are regulatory • microRNAs can bind to complementary sequences in RNA • What would a double-stranded RNA molecule do?

  22. Mechanism for RNA interference (RNAi) miRNA siRNAs do the same thing but are formed differently These can affect chromatin packing

  23. Embryonic development and regulated gene expression • One cell gives rise to many • The cells are not the same • Differentiate into organs and tissues • Morphogenesis- change in form • How, when, and where?

  24. Different cells activate different genes • Process is sequential • Cell differentiation is a pathway • End product: a specialized cell

  25. The information is in the egg

  26. The sequential process of cell differentiation (in the right environment)

  27. How do the cells develop in the right place? Many genes required for body plan formation

  28. Cancer: when cell cycle control goes wrong • Proto-oncogenes: the accelerator • Tumor suppressor genes: the brakes • DNA repair • Anchoring of cells • Regulatory pathways

  29. Pathways, and some important regulatory genes

  30. Cancer does not happen easily

  31. …but risk factors can increase your chances of cancer • Inherited mutations (one “hit” has already happened) • APC • p53 • BRCA 1 • Exposure to DNA-damaging substances • Certain types of viruses

  32. Summary • Bacteria can regulate transcription through operons • Eukaryotic gene expression is (surprise!) more complex • “noncoding” RNAs are newly-discovered regulators of gene expression • Cell differentiation and development is a function of gene expression • Cancer develops from loss of cell cycle control

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