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Edinburgh Pathway Notation

Edinburgh Pathway Notation. Stuart Moodie. Overview. SBGN SBGN-1 Graphical Notations EPN Interferon Pathway Biology Notation details. SBGN ( www.sbgn.org ). Aims Agree a standard set of notations Develop tools to support SBGN Encourage community usage Members include:

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Edinburgh Pathway Notation

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  1. Edinburgh Pathway Notation Stuart Moodie

  2. Overview • SBGN • SBGN-1 • Graphical Notations • EPN • Interferon Pathway Biology • Notation details

  3. SBGN (www.sbgn.org) • Aims • Agree a standard set of notations • Develop tools to support SBGN • Encourage community usage • Members include: • Hiroaki Kitano (Systems Biology Institute) • SBML community • BioPAX community • Cytoscape • University of Edinburgh

  4. SBGN-1 • Tokyo Feb 2006

  5. Graphical Notations Overview

  6. Why do we need them?

  7. The Need • Unambiguous descriptions • Describe pathway behaviour to biologists • Understand gaps in knowledge • Stand back from the detail • Get the big picture • Describe pathway behaviour to computer • Model pathways • Create and test hypotheses in silico

  8. Use Circuit Diagrams?

  9. Pathways are not Electronic Circuits • Circuits designed by humans • Follow a defined set of rules • Boundaries well defined • Pathways • Don’t know all the “rules” • Boundaries not clear • Knowledge often incomplete

  10. Types of Graphical Notation • Entity Relationship • Protein Interaction Diagrams • MIM (Kohn) • State Transition • EPN • PDN (Kitano)

  11. Entity Relationship View

  12. MIMs • Inspired by circuit diagrams • Invented by Kurt Kohn, NIH • First published 1999 • Presented to SBGN by Marit Aladjem • Slides taken from Aladjem presentation at SBGN-1

  13. Cyclin A/B Cdk1 D N A ( o r i ) Assembly of a multimolecular complex: ORC, the origin recognition complex (involved in cell cycle regulation)

  14. A B C The complex of (A&B) & C Multi-protein complexes Each molecule appears only once per diagram. Interaction outcomes - complexes or modified molecules - are depicted as nodes on the interaction lines.

  15. A B Catalysis line convention P Inhibition convention Inhibitory phosphorylation: Phosphorylation of A blocks the kinase activity of A. Covalent modification (e.g., protein phosphorylation) P P = PO4, a phosphate group

  16. A B P Bar added to indicate obligatory requirement Activating phosphorylation: The phosphorylated form of kinase A is the active form, phosphorylates B P

  17. Contingencies Dimerization Binding (non-covalent) Covalent Modification (e.g. phosphorylation) A B A A Catalysis Stimulation Bond cleavage (e.g. Phosphatase) Stimulation required Inhibition Transcription/translation Transport Reactions Reactions operate on molecular species; contingencies operate on reactions, or on other contingencies; reaction outcomes (nodes) are treated as molecular species. Stochiometric Conversion (A to B) Degradation

  18. MIMs • Benefits • Compact • Established • Useful to biologists • Drawbacks • Learning curve • No tool support

  19. State Transition Diagrams PDN & EPN

  20. State Transition

  21. Slides taken from Kitano presentation at SBGN-1

  22. PDN (Kitano Notation)

  23. PDN (Kitano) Notation • Benefits • Simple – easy to learn • Maps easily to SBML • Established • Tool support (CellDesigner, EPE) • Drawbacks • Verbose (takes up a lot of space) • Need to know pathway in detail

  24. Edinburgh Pathway Notation EPN

  25. Interferon Pathway Biology Project • Interferon response pathway in macrophage • Have collated >200 components of pathway from literature • 3 years of MSc students • Each interaction has provenance info • Developing scoring scheme

  26. Objectives • To develop new approaches and understanding in Pathway Biology of infection and innate immunity • Integration of HTP experimental data (high dimensional biology) with in silico pathway analysis • Build a knowledge base using consensus pathway and logic interactions

  27. Notation • Use graphical representation of pathway • Evolved a notation through use

  28. Extracellular space Irf3 Trail TNFa Extracellular Antigen D68 Endocyt. Ag-pep Cytosolic Ag-pep HLA- DRB HLA- DRB HLA- DRB HLA- DRB B2m HLA- A/B/C HLA-DRA HLA-DRB H2-DMa: H2-DMb H2-Oa: H2-Ob Endocyt. Ag-pep HLA-A/B/C B2m HLA-DRA HLA-DRB Trail-R1/2 Tnfr1 Clip Ii Clip Cytosolic Ag-pep Cell membrane D69 D70 D70 Ingoing endosome D66 Endocyt. Ag-polypep Endocytosed Antigen Endocyt. Ag-pep Kpna3 Kpna4 + D67 Late outgoing endosome membrane Ctss Ctsb Ctsd Late outgoing endosome lumen Fadd Psmb8 Psmb8 D71 P Pact Psma(1-7): Psmb(1-4): Psmb(1-4): Psmb(1-7) Psma(1-7): Psmb(1-4): Psmb(1-4): Psma(1-7) Psmb9 Psmb9 D72 dsRNA Psmb10 Psmb10 Ikbke Tbk1 D73 Casp8 Psme1 Psme2 Psme1(7) Psme2 B73 B74 D74 Ser51 P P IAD eIF2-a B75 Cytosol Irf7 Psme1(7) Psme2 P IAD B76 Psmb8 D77 D76 Irf1 D75 P Oas STAT1 Casp7 Irf7 Irf7 P Psma(1-7): Psmb(1-4): Psmb(1-4): Psma(1-7) Psmb10 Psmb9 P Irf3:Irf3 IAD B77 Irf3 Psmb9 Psmb10 P 2,5A + IAD B78 Irf5 NF-kB Complex Psmb8 Psme1(7) Psme2 B79 Apaf-1 STAT1 B61 Casp1 P Ikbke Tbk1 D78 Bax C2ta Irf3:Irf3 B58 B59 Cytosolic Antigen Cytosolic Ag-pep Bax P P Ser Ser B60 Irf3 Irf3 Mitochondrial membrane Ii B2m HLA- A/B/C HLA- DRB HLA- DRB Bak Ctsd Cytosolic Ag-pep Ctsb Endocytosed Antigen Endocytosed Antigen Mitochondiral lumen B64 Ctss + D65 Lysosome membrane Ctsh D64 + HLA- DRB Ii HLA- DRB B2m HLA- A/B/C H2-DMa: H2-DMb Cytosolic Ag-pep Ctsb H2-Oa: H2-Ob Ctss D63 Lysosome lumen + Early outgoing endosome membrane B2m HLA- A/B/C H2-DMa: H2-DMb HLA- DRB Ii HLA- DRB Cytosolic Ag-pep Ctss H2-Oa: H2-Ob Early outgoing endosome lumen Golgi membrane P P Ep300 P Irf7 Irf1 Golgi lumen P P Irf7 Irf5 & Irf3:Irf3 ER-cytosol mem-brane Crebbp D80 Tap1 Tap2 Tap1: Tap2 D81 P P D60 D82 Irf3 Irf7 P P D79 B2m H2-DMa: H2-DMb B2m Ii & Irf7 Irf7 HLA-DRB HLA-DRA H2-DMa: H2-DMb & Cytosolic Ag-pep HLA- A/B/C HLA- A/B/C Cytosolic Ag-pep H2-Oa: H2-Ob H2-Oa: H2-Ob D61 D61 D62 ER Lumen Cytosolic Ag-pep HLA-DRA Ii HLA-DRB Ctss HLA-B B2m HLA-C HLA-A P P P T Stat1 Ifna14 Stat2 Nuclear membrane XPO1 + T Ifna7 B63 NES HLA-C HLA-A HLA-B B2m Ii HLA-DRB Tap1 Tap2 HLA-DRA Ctss T Casp8 Ifna4 Bak Bcl-2 Bcl-xL D38 D44 Hmga1 Tap1 Tap2 Ii HLA-DRB HLA-DRA HLA-B D33 HLA-C HLA-A Ctss T T T T D39 D45 RnaseL Irf3:Irf3 B2m & T T T & T & + T T Casp8 T T Bcl-2 Bcl-xl Bak & + T & + D25 D26 D27 D28 D24 D29 B62 D31 D32 D35 D36 D37 D41 D42 D43 D47 D48 D49 D50 D51 D52 D53 D40 D46 D30 D34 Irf1 Irf2 Irf4 Icsbp1 B80 Prkr Atf2:Jun Stat1:Stat1 B87 T Psmb9 Hist4h4 B65 D54 T Psmb9 B88 B66 B89 B83 B84 Prkr B81 T B86 B8 B85 B82 B67 B54 D55 B86 Tnfsf6 Tnfrsf6 Nucleoplasm B84 ISRE B55 T ISRE Ifna11 IFNg T PRDIV | G1p2 T T & D23 Ccl5 Tnfrsf6 T Ifna1 PRDII Tnfsf6 Usf2 + & * T B57 PRDIII Psmb8 Psmb10 Nfya Crebbp Oas Psmb8 Psmb10 Usf1 D13 D15 IRF7 Rfxank Rfxap Myc PRDI Nfkb1 T T ISRE Nfkb1-Rela D14 ISRE T Nfyc D56 D57 B11 Usf1 B21 T D16 Oas D11 Ep300 Rela D17 Psme1 Psme2 D19 D10 D22 B22 Rfx5 B56 Psme1 Psme2 T D12 D20 Nfyb C2ta Stat2 B47ii T T GAS B1 D21 D18 Creb1 D59 D58 T D6 B30 Irf1 S133 Crebbp Pcaf P Pcaf Irf1 K141 D7 B17 Ac B31 T C2ta K144 D8 Icsbp1 Irf2 Ac GAS T Irf2 Irf4 Ac Ac D1 B39 Tyr220 Tyr226 PEST C2ta P & P Ser P D2 Icsbp1 T & D3 B37 B34 D4 B26 PEST PEST B40 T D5 Stat1 B12 Stat6 Fkbp4 Sfpi1 B42 B27 B35 B36 B41 B47i B13ii B48 CD23b GAS B13i ETS + T B15 * T Itgam T Fcer2a Il1b B33 * T B44 B43 Il12b B14 B46 B45 B38 B52 B49 B29 B24 B16 IRF-E T T Cdkn1a Cybb T Il12a C1 * Interferon Subcellular Logic Interaction Map Ifng Ifng A54 A1 C6 Ifna Ifnb C2 & C65 A35 A36 A2 | Tnfsf6 = A37 C7 C5 C8 A3 A4 Y466 P Fnrsf6 Ifngr2 Ifngr1 Ifnar1 Ifnar2 C64 P Y440 A42 A40 A47 A16 A10 A51 A5 A8 C10 C9 A67 C11 Tyk2 Jak1 Jak2 Map2k1/ Map3k1 A44 Ptk2b A60 P A7 C12 P Hrmt1l2 Tradd P Au P A52 A41 P A46 A6 A38 A55 A55 A43 Ifng | PRKR C14 P A53 Pias1 P P P Map2k1 C13 MAPKK (Identity not Known) Map2k2 Vav STAT1 A11 Y701 NLS A12 A13 Prkcd | STAT1 P = A39 A65 SH2 domain Arg31 A56 A56 M C4 C19 Caspases Effectors C55 & & A9 GTP P GDP P S727 A59 Rac1 Mapk3 Mapk1 C17 P C18 A48 + + CASP8 Y690 Camk2a C15 A15 Stat1 P Prkr SH2 domain Stat2 A21 | Casp3 CASP9 A62 A45 A59 A34 A20 | C24 C16 C25 Mapk14 C20 A14 C53 A49 A64 A57 C54 STAT1 C62 C56 A17 Cebpb C23 PRKR C21 C22 I-kB C48 P C35 C57 A58 A58 C3 PRKR C66 2,5A System C49 Kpna1 & Casp9 A18 C34 & & C36 Ran A19 Isgf3g Isgf3g Caspases Initiators A22 C52 & C50 & WD40 Domain NLS NLS Cyt.C A50 A50 C33 C56 C32 C28 C31 NF-kB Complex Bcl-xL C26 C27 Cause Release of Cyt.C C30 C29 Inhibit Release of Cyt.C Bcl-2 Cyt.C Isgf3g Isgf3g Isgf3g Isgf3g T A23 P A24 | & & Stat1 A23 + + A32 A23 A27 Y701 A32 Isgf3g Stat2 P A25 Nmi | P P P P A26 Y701 Stat1 Stat1 Y701 B72 + & + & Tradd A32 ISRE & & + A22 A22 A27 + + MCM5 A27 + T | A33 A27 A33 NF-kB complex Casp7 Casp1 Casp3 Sp1 A28 + | T Casp8 T T C51 Casp8 Casp3 Casp7 Casp1 Casp7 TNFRSF6 TNFSF6 BRCA1 C58 A30 C38 C37 C39 | | STAT1 C57 B9 C40 B32 B6 STAT1 (=C42) (=C43) (=C41) A31 TFII-I A31 STAT1 STAT1 Gtf2i A66 B4 C44 B25 C60 C45 C46 C47 B23 D9 B5 IRF1 IRF1 IRF1 IRF1 IRF1 B10 ICSBP1 B2 A32 Isgf3g Isgf3g Isgf3g Isgf3g GAS GAS A33 B3 T T GATE GATE MSE MSE B50 DNA Degradation, ,Cell shrinkage and Membrane blebbing etc Protein Synthesis Inhibition Apoptosis RNA Degradation

  29. Aims of Notation • Accessible to biologists • Described logic of interactions • Compact • Showed subcellular localisation clearly • Tolerant of incomplete knowledge • Computable • Software tools • Maps to SBML

  30. Design Principles • Describe state of interacting species • Localisation, Complexes, Activation, Modification • Minimise redundancy • Minimise number of symbols and concepts to remember • Focus on logic

  31. Different Views Edinburgh Pathway Notation Logical Metabolic PDN Biochemical

  32. State Transition/Activation

  33. Logic Gates

  34. Complex Formation

  35. Gene Regulation

  36. Gene Regulation: Multiple States

  37. Localisation Outside Inside

  38. Symbols

  39. State transition: the hidden details • Kitano process notation

  40. State Details

  41. Complex Details

  42. Tool Support: EPE • Supports full notation • Supports Kitano notation • Hyperlinks to sub-diagrams • Generates SBML map of notation

  43. Jak/Stat

  44. Benefits • Simple • Compact • Quick to draw large maps • Enables hierarchical organisation • Links to biochemical notation • Software support

  45. Future Work • Continue “Field test” notation • Metabolic pathways • mRNA regulation (miRNA) • Pathway “modules”

  46. GTI Peter Ghazal Stuart Moodie Alan J. Ross Garwin Sing Kevin Robertson Paul Dickinson Graeme Grimes Thorsten Forster Douglas Roy John Beattie ECB Igor Goryanin Anatoly Sorokin Collaborators Dirk Husmeier Adriano Velasque Lily Cho Tobias Frankenberg Li-kun Phng Zhenjie Xu Lee Chuin Yao Alex Selkov Acknowledgements

  47. Questions?

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