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Transcription regulation of complex loci

Transcription regulation of complex loci . David Arnosti Dept. Biochemistry & Molecular Biology Michigan State University. Pioneers of the 19th century. Pioneers of the 21st century. A biologist’s wish list: “Parts list” operational system description. A biologist’s wish list:

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Transcription regulation of complex loci

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  1. Transcription regulation of complex loci David Arnosti Dept. Biochemistry & Molecular Biology Michigan State University

  2. Pioneers of the 19th century

  3. Pioneers of the 21st century

  4. A biologist’s wish list: “Parts list” operational system description

  5. A biologist’s wish list: “Parts list” operational system description Predict function of cis regulatory sequences

  6. A biologist’s wish list: “Parts list” operational system description Predict function of cis regulatory sequences Build picture of transcriptional regulatory networks

  7. A biologist’s wish list: “Parts list” operational system description Predict function of cis regulatory sequences Build picture of transcriptional regulatory networks Understand dynamic properties of system; effect of changes/mutations on output

  8. Tuesday: Transcriptional regulation of complex loci Wednesday: Transcriptional logic machines for developmental patterning

  9. Study the Form or the shadows on the cave wall?

  10. Compact regulatory regions in yeast db.yeastgenome.org/cgi-bin/gbrowse/yeast/

  11. Dispersed regulatory regions in animals Merli et al. (1996) Genes Dev. 10:1260

  12. specifics, qualitative Evolution Bioinformatics, modeling Three lenses: Biochemistry general, quantitative

  13. A word about genetic information…

  14. Make a bit of RNA and thread it through a ribosome! Protein Coding M P Q Q 5’ 3’ AUGCCCCAGCAG • Information content dictated by • 5’-3’ orientation • Position with respect to an AUG • Phase (reading frame) • Location distal to a transcriptional start site

  15. Regulatory Regulatory regions are bound by transcription factors Complexity stems from information being “read out” as nucleoprotein complexes of various structure and function.

  16. Regulatory Move gene to particular nuclear compartment

  17. Regulatory Move gene to particular nuclear compartment Modify the chromatin structure of the gene

  18. Regulatory Move gene to particular nuclear compartment Modify the chromatin structure of the gene

  19. Regulatory Move gene to particular nuclear compartment Modify the chromatin structure of the gene Directly contact components of the basal machinery

  20. Regulatory Move gene to particular nuclear compartment Modify the chromatin structure of the gene Directly contact components of the basal machinery 4. Influence the binding of cofactors

  21. Outline 1. Definitions 2. eve - one gene/multiple enhancers 3. Globin locus - one enhancer/multiple genes 4. HOX genes - boundaries & memory modules 5. Enhancer-promoter trafficking and boundary elements

  22. Promoter Enhancer Silencer Boundary Element “Cis regulatory element”

  23. Outline 1. Definitions 2. eve - one gene/multiple enhancers 3. Globin locus - one enhancer/multiple genes 4. HOX genes - boundaries & memory modules 5. Enhancer-promoter trafficking and boundary elements

  24. figures from Steve Small, NYU Body segmentation is presaged by segmental gene expression.

  25. 7 6 3 4 5 2 1 figure from Steve Small, NYU

  26. eve expression pattern evolves from broad pattern to stripes

  27. Generalized activation

  28. giant Positional specification is dictated by transcriptional repressors Refinement through repression

  29. ? Modularity of enhancers depends on short-range of transcriptional repression

  30. Short-range repressors Long-range repressors

  31. Short-range repressors Long-range repressors giant knirps Kruppel snail <100 bp

  32. Short-range repressors Long-range repressors giant knirps Kruppel snail hairy Dorsal repression complexes <100 bp >1,000 bp

  33. hair y knirp s Short-range Long-range

  34. CtB P groucho hair y knirp s Short-range Long-range

  35. Histone Deacetylases CtB P groucho hair y knirp s Short-range Long-range

  36. Histone Deacetylases CtB P groucho hair y knirp s Short-range Long-range

  37. Histone Deacetylases CtB P groucho hair y knirp s Short-range Long-range

  38. stripe 2 enhancer eve

  39. Two Models for Enhancer Design Enhanceosome -“smart but high-strung” IFN-ß enhancer Billboard - “dumb but flexible” developmentally regulated enhancers

  40. Enhanceosome • - extensive cooperative interactions • constrained placement of binding sites • monolithic activation (repression) complex Kulkarni and Arnosti, Development 130, 6569.

  41. Billboard (information display) • - cis element provides loose grouping • multiple subelements - apparent redundancy • - overall output - integration over time of enhancer “sampling” Kulkarni and Arnosti, Development 130, 6569.

  42. Ludwig et al. (2000) Nature 403, 567.

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