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Computational Molecular Biology Biochem 218 – BioMedical Informatics 231 Gene Regulatory.

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1 Computational Molecular Biology Biochem 218 – BioMedical Informatics 231 http://biochem218.stanford.edu/ http://biochem218.stanford.edu/ Gene Regulatory Networks Doug Brutlag Professor Emeritus Biochemistry & Medicine (by courtesy)

2 Homework 7 Transcription Factor Motifs for Co-expressed Genes Choose a group of co-expressed genes from the Yeast Cell Cycle Database by first entering a single gene of interest to you and then clicking on select all co- expressed genes: http://genome-www.stanford.edu/cgi-bin/cellcycle/search Collect all the names of the genes and enter them in Go Term Finder to discover common biological processes, common molecular mechanisms and common cellular components in the Saccharomyces Genome Database: http://www.yeastgenome.org/cgi-bin/GO/goTermFinder.pl Using the Batch download link, collect all the gene sequences plus 1 KB upstream and enter the 1 KB upstream sequence from all the genes into MDScan and search for motifs 8, 10 or 12 bases long: http://mdscan.stanford.edu/ You may have to remove simple sequences such as (tatatatata or tttttttttt or cacacacaca) by globally replacing them with an X character in order to ignore simple sequence repeats from the list of motifs found. Enter your list of co-expressed gene names in YeasTract web site and see if MDScan has discovered any known transcription binding sites: http://www.yeast ract.com/

3 Yeast Cell Cycle Database http://genome-www.stanford.edu/cgi-bin/cellcycle/search http://genome-www.stanford.edu/cgi-bin/cellcycle/search

4 Yeast Cell Cycle Database http://genome-www.stanford.edu/cgi-bin/cellcycle/search http://genome-www.stanford.edu/cgi-bin/cellcycle/search

5 Yeast Cell Cycle Database http://genome-www.stanford.edu/cgi-bin/cellcycle/search http://genome-www.stanford.edu/cgi-bin/cellcycle/search

6 Saccharomyces Genome Database http://www.yeastgenome.org/ http://www.yeastgenome.org/

7 Saccharomyces Genome Database Go Term Finder http://www.yeastgenome.org/ http://www.yeastgenome.org/

8 Saccharomyces Genome Database Go Term Finder Results

9 Saccharomyces Genome Database Gene Sequence Resources http://www.yeastgenome.org/cgi-bin/seqTools http://www.yeastgenome.org/cgi-bin/seqTools

10 Saccharomyces Genome Database Batch Download Tool http://www.yeastgenome.org/cgi-bin/batchDownload http://www.yeastgenome.org/cgi-bin/batchDownload

11 Saccharomyces Genome Database Batch Download Tool http://www.yeastgenome.org/cgi-bin/batchDownload http://www.yeastgenome.org/cgi-bin/batchDownload

12 MDScan http://mdscan.stanford.edu/ http://mdscan.stanford.edu/

13 MDScan Input http://mdscan.stanford.edu/ http://mdscan.stanford.edu/

14 MDScan Output

15 YeasTract Transcription Factor Database http://www.yeastract.com/ http://www.yeastract.com/

16 YeasTract Transcription Factor Search http://www.yeastract.com/formfindregulators.php http://www.yeastract.com/formfindregulators.php

17 YeasTract Transcription Factor Search Results http://www.yeastract.com/formfindregulators.php http://www.yeastract.com/formfindregulators.php

18 What is Systems Biology? http://en.wikipedia.org/wiki/Systems_biology http://en.wikipedia.org/wiki/Systems_biology

19 What is Systems Biology? Systematic approach to biology o Protein networks involving all protein-protein interactions o Metabolic networks involving all enzymes & pathways o Gene regulation involving all regulatory interactions o Cell behavior involving all environmental responses o Population biology involving all selectable traits. Challenges of System Biology o Identifying all selectable traits, all regulatory interactions, all protein complexes, all metabolic pathways, all regulatory pathways, all selectable traits o Computationally representing and simulating cell structures, metabolism, regulation, behavior and selection o Usually approached by simplification, studying one protein complex, one metabolic pathway, one regulatory network or one trait at a time. Then combining individual examples to represent the entire cell or organism.

20 Yeast Protein Interaction Network H. Jeong, et al., Nature, Vol 411, p41 (2001) H. Jeong, et al., Nature, Vol 411, p41 (2001)

21 Yeast Protein Interaction Network H. Jeong, et al., Nature, Vol 411, p41 (2001) H. Jeong, et al., Nature, Vol 411, p41 (2001)

22 Evolutionary Rate in the Protein Interaction Network Fraser, et al. Science 296, p750 (2002)

23 Yeast Metabolic Pathways http://biocyc.org/ http://biocyc.org/ © Peter Karp, 2008, http://biocyc.org/

24 Yeast Gene Regulatory Networks Lee et al. Science 298, 799-804 (2002)

25 Genomics Provides Location and number of genes o By mapping messenger RNAs (cDNAs or ESTs) o By computational gene finding programs By computational gene finding programs  Glimmer Glimmer  GenScan GenScan  Grail & Grail EXP Grail & Grail EXP  FGENESH FGENESH  GeneMark & GenMarkHMM GeneMark GenMarkHMM o By homology and conservation By homology and conservation Gene expression and regulation information o From tissue specific mRNAs (cDNAs or ESTs) o From DNA chips or microarrays  Gene probes and tiling arrays o ChIP-Chip experiments o Stanford Microarray Database Stanford Microarray Database o NCBI GEO NCBI GEO o EBI ArrayExpress EBI ArrayExpress Gene regulatory sequences o Promoter signals near beginning (5’ end) of transcripts o Transcription factor binding sites o Transcription start sites (TSS) o Transcription termination signals (TTS) o RNA processing signals  Splice donor and acceptor sites  5’ Cap site  3’ polyAdemylation

26 Eukaryotic Gene Structure miRNA Target

27 Multiple Enhancer Sequences

28 Gene Expression Regulatory Network

29 Interferon-beta Gene Enhanceosome http://www.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb122_1.html http://www.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb122_1.html

30 Interferon-beta Enhanceosome http://www.cell.com/retrieve/pii/S0092867407006563 http://www.cell.com/retrieve/pii/S0092867407006563

31 IFN-beta Enhanceosome & Enhancer http://www.cell.com/retrieve/pii/S0092867407006563 http://www.cell.com/retrieve/pii/S0092867407006563

32 IFN-beta Enhancer http://www.cell.com/retrieve/pii/S0092867407006563 http://www.cell.com/retrieve/pii/S0092867407006563

33 Enhanceosome: Exploring the Structure http://www.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb122_2.html http://www.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb122_2.html

34 IL7 Regulatory Pathway http://www.biocarta.com/pathfiles/h_pcafpathway.asp http://www.biocarta.com/pathfiles/h_pcafpathway.asp © BioCarta

35 IL7 Regulatory Pathway http://www.biocarta.com/pathfiles/h_il7Pathway.asp/ http://www.biocarta.com/pathfiles/h_il7Pathway.asp/ © BioCarta

36 Growth Hormone Receptor Pathway http://www.biocarta.com/pathfiles/h_ghPathway.asp/ http://www.biocarta.com/pathfiles/h_ghPathway.asp/ © BioCarta

37 Gene Regulatory Mechanisms Transcriptional Mechanisms o Type of promoters & RNA polymerase o Control of Transcription  Constitutive  Inducible  Repressible o Transcription Factors and TFBS RNA processing o Capping o Splicing and Alternative Splicing o Poly-Adenylation o RNA export to cytoplasm o RNA degradation rates Translational Mechanisms o Micro RNAs (miRNAs) o Silencer RNAs (siRNAs or RNAi) degrading mRNA Epigenetic Mechanisms o DNA methylation at CpG sites o Histone acetylation o Chromatin remodeling

38 Measuring Gene Expression with DNA Microarrays and cDNA Labeling Cy3Cy5

39 ChIP-Chip Methodology

40 ChIP-Chip Identification of Transcription factor Binding Sites Lee et al. Science 298, 799-804 (2002)

41 Distribution of TFBS Among 6300 Promoters Lee et al. Science 298, 799-804 (2002)

42 Network Motifs in Yeast Regulatory Networks Lee et al. Science 298, 799-804 (2002)

43 Yeast Cell Cycle Regulatory Motifs Lee et al. Science 298, 799-804 (2002)

44 Yeast Regulatory Motifs Lee et al. Science 298, 799-804 (2002)

45 Transcription Factor Binding Site Specificities http://web.wi.mit.edu/young/regulatory_code/ http://web.wi.mit.edu/young/regulatory_code/ Harbison et al, Nature 431, 99-104 (2004)

46 Yeast Regulatory Map http://web.wi.mit.edu/young/regulatory_code/ http://web.wi.mit.edu/young/regulatory_code/ Harbison et al, Nature 431, 99-104 (2004)

47 Yeast Regulatory Map http://web.wi.mit.edu/young/regulatory_code/ http://web.wi.mit.edu/young/regulatory_code/ Harbison et al, Nature 431, 99-104 (2004)

48 Yeast Promoter Architecture http://web.wi.mit.edu/young/regulatory_code/ http://web.wi.mit.edu/young/regulatory_code/ Harbison et al, Nature 431, 99-104 (2004)

49 Environment Specific Regulators http://web.wi.mit.edu/young/regulatory_code/ http://web.wi.mit.edu/young/regulatory_code/ Harbison et al, Nature 431, 99-104 (2004)

50 YeasTract Transcription Factor Database http://www.yeastract.com/ http://www.yeastract.com/

51 YeasTract Transcription Factor Search http://www.yeastract.com/formfindregulators.php http://www.yeastract.com/formfindregulators.php

52 YeasTract Transcription Factor Search Results http://www.yeastract.com/formfindregulators.php http://www.yeastract.com/formfindregulators.php

53 YeasTract UpStream Sequences http://www.yeastract.com/formseqretrieval.php http://www.yeastract.com/formseqretrieval.php

54 YeasTract UpStream Sequences Retrieval http://www.yeastract.com/formseqretrieval.php http://www.yeastract.com/formseqretrieval.php

55 YeasTract Motif Discoverer http://www.yeastract.com/discoverer/ http://www.yeastract.com/discoverer/

56 YeasTract Motif Discoverer Results http://www.yeastract.com/discoverer/ http://www.yeastract.com/discoverer/

57 YeasTract Transcription Factor Associations http://www.yeastract.com/formregassociations.php http://www.yeastract.com/formregassociations.php

58 YeasTract Transcription Factor Associations http://www.yeastract.com/formregassociations.php http://www.yeastract.com/formregassociations.php

59 YeasTract Group Genes by Go Terms http://www.yeastract.com/formregassociations.php http://www.yeastract.com/formregassociations.php

60 YeasTract Group Genes by Go Terms http://www.yeastract.com/formregassociations.php http://www.yeastract.com/formregassociations.php

61 Swiss Regulon http://www.swissregulon.unibas.ch/cgi-bin/regulon http://www.swissregulon.unibas.ch/cgi-bin/regulon

62 Swiss Regulon Organisms http://www.swissregulon.unibas.ch/cgi-bin/regulon http://www.swissregulon.unibas.ch/cgi-bin/regulon

63 Swiss Regulon Yeast TF Binding Sites Near Pol30 http://www.swissregulon.unibas.ch/cgi-bin/gbrowse/yeast/ http://www.swissregulon.unibas.ch/cgi-bin/gbrowse/yeast/

64 Swiss Regulon Yeast Transcription Factor Ste12 http://www.swissregulon.unibas.ch/cgi-bin/gbrowse/yeast/ http://www.swissregulon.unibas.ch/cgi-bin/gbrowse/yeast/

65 Swiss Regulon Yeast Transcription Factor Ste12 Sites http://www.swissregulon.unibas.ch/cgi-bin/gbrowse/yeast/ http://www.swissregulon.unibas.ch/cgi-bin/gbrowse/yeast/

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