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Objectives

Eukaryotic Gene Regulation April 23, 2014 Richard D. Howells, PhD MSB E-643 howells@njms.rutgers.edu. Objectives. During this presentation you may Catch another 40 winks, or Understand key concepts regarding regulation of gene expression in eukaryotes. Eukaryotic RNA Polymerases. 3.

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Objectives

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  1. Eukaryotic Gene Regulation April 23, 2014Richard D. Howells, PhDMSB E-643howells@njms.rutgers.edu

  2. Objectives During this presentation you may • Catch another 40 winks, or • Understand key concepts regarding regulation of gene expression in eukaryotes

  3. Eukaryotic RNA Polymerases 3

  4. Eukaryotic RNA polymerases The poisonous mushroom, Amanita phalloides, contains -amanitin, a cyclic octapeptide that blocks elongation by RNA Pol II. It is lethal at 10 nM. The initial reaction to ingestion of the mushroom is gastrointestinal distress, and 48 h later the subject dies, usually from liver dysfunction. 4

  5. Amanita phalloides: the Death Cap 5

  6. tRNA processing

  7. Eukaryotic Promoter Elements

  8. Pol IIpreinitiation complex

  9. RNA Pol II Preinitiation Complex 10

  10. General pattern of control elements that regulate gene expression in multicellular eukaryotes and yeast From Transcriptional Control Of Gene Expression, Molecular Cell Biology, Lodish et al., eds., 6th edition

  11. Model for regulated gene expression

  12. Hormones that bind specific receptors that are stimulated to become ligand-activated transcription factors These and related lipid-soluble hormones bind to receptors located in the nucleus and cytoplasm. The hormone-receptor complex functions as a transcription factor in the nucleus.

  13. Select members of the nuclear receptor family The centrally located DNA binding domains each contain 2 copies of the zinc finger motif. Ligand binding domains are C-terminal, and N-termini often contain activation domains.

  14. Zinc-finger domain

  15. DNA response elements that bind nuclear receptors Repeat sequences are indicated by red arrows.

  16. Hormone-dependent gene regulation by glucocorticoid receptor AD: activation domain; DBD: DNA binding domain; LBD: ligand binding domain

  17. Activation of gene expression via elevated cAMP and phosphorylation of CREB CRE: cAMP response element; CREB: CRE binding protein; CBP: CREB binding protein

  18. Mutation of CBP causes pleiotropic developmental abnormalities:Rubinstein-Taybi syndrome

  19. Regulation of gene expression via post-translational modification of histone side chains Acetylated Lysine Lysine HAT: histoneacetyltransferase activity HDAC: histonedeacetylase activity

  20. Histone acetylation/deacetylation in transcriptional control of gene expression The transcriptional activator Gcn5 has histoneacetyltransferase activity

  21. Histone acetylation/deacetylation in transcriptional control of gene expression The transcriptional repressor Rdp3 has histonedeacetylase activity

  22. Intron 1 Example: Developmental-Temporal Regulation of Factor IX Transcription Factor IX Transcribed Region AR HNF4 Exon 1 AR binding site HNF4 binding site • Factor IX is a blood clotting factor • Mutation at –20 cause Hemophilia B Leyden • Reduces HNF4 binding (Hepatocyte Nuclear Factor 4) • Factor IX levels increase with onset of puberty due to testosterone production • Mutation at –26 causes Hemophilia B Brandenburg • Reduces HNF4 binding and androgen receptor (AR) binding • Factor IX levels remain low throughout life

  23. Overview of mRNA processing in eukaryotes 25

  24. Structure of the 5’-methylated cap of eukaryotic mRNA 26

  25. Model for cleavage and polyadenylation of pre-mRNAs in mammalian cells CPSF- cleavage and polyadenylation specificity factor CStF- cleavage stimulatory factor CFI,CFII- cleavage factors PAP- poly(A) polymerase PABP II- poly(A) binding protein 27

  26. 28

  27. Model of spliceosome-mediated pre-mRNA splicing 29

  28. Micro RNAs and short interfering RNAs 30

  29. Pathways for degradation of eukaryotic mRNAs 31

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