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Regulatory network operations in the Pathway Tools software.

Paley SM, Latendresse M, Karp PD - BMC Bioinformatics (2012)

Bottom Line: We introduce a novel type of enrichment analysis that asks whether a gene-expression dataset is over-represented for known regulators.We present algorithms for ranking the degree of regulatory influence of genes, and for computing the net positive and negative regulatory influences on a gene.Pathway Tools provides a comprehensive environment for manipulating molecular regulatory interactions that integrates regulatory data with an organism's genome and metabolic network.

View Article: PubMed Central - HTML - PubMed

Affiliation: Bioinformatics Research Group, SRI International 333 Ravenswood Ave, Menlo Park, CA 94025, USA.

ABSTRACT

Background: Biologists are elucidating complex collections of genetic regulatory data for multiple organisms. Software is needed for such regulatory network data.

Results: The Pathway Tools software supports storage and manipulation of regulatory information through a variety of strategies. The Pathway Tools regulation ontology captures transcriptional and translational regulation, substrate-level regulation of enzyme activity, post-translational modifications, and regulatory pathways. Regulatory visualizations include a novel diagram that summarizes all regulatory influences on a gene; a transcription-unit diagram, and an interactive visualization of a full transcriptional regulatory network that can be painted with gene expression data to probe correlations between gene expression and regulatory mechanisms. We introduce a novel type of enrichment analysis that asks whether a gene-expression dataset is over-represented for known regulators. We present algorithms for ranking the degree of regulatory influence of genes, and for computing the net positive and negative regulatory influences on a gene.

Conclusions: Pathway Tools provides a comprehensive environment for manipulating molecular regulatory interactions that integrates regulatory data with an organism's genome and metabolic network. Curated collections of regulatory data authored using Pathway Tools are available for Escherichia coli, Bacillus subtilis, and Shewanella oneidensis.

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Sample regulation summary diagrams for E. coli . a) The trpD diagram shows inhibition by TrpR (a homodimer, as indicated by the appearance of multiple stacked copies) bound to tryptophan, attenuation by tryptophanyl-tRNA, and substrate-level regulation of the final complex by tryptophan. b) The oppD diagram shows inhibition by several transcription factors (the leucine ligand blocks regulation by Lrp), and regulation of translation by a spermidine riboswitch and RNA GcvB with accessory protein Hfq (a homosexamer). c) The glnG diagram shows activation and dual regulation by several transcription factors, and post-translational modification triggered by phosphorylated NtrB.
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Figure 4: Sample regulation summary diagrams for E. coli . a) The trpD diagram shows inhibition by TrpR (a homodimer, as indicated by the appearance of multiple stacked copies) bound to tryptophan, attenuation by tryptophanyl-tRNA, and substrate-level regulation of the final complex by tryptophan. b) The oppD diagram shows inhibition by several transcription factors (the leucine ligand blocks regulation by Lrp), and regulation of translation by a spermidine riboswitch and RNA GcvB with accessory protein Hfq (a homosexamer). c) The glnG diagram shows activation and dual regulation by several transcription factors, and post-translational modification triggered by phosphorylated NtrB.

Mentions: The Regulation Summary Diagram provides a compact and information-rich overview of all the direct regulatory influences on a single gene product, from transcription and translation to post-translational modifications and substrate-level modulation. Some examples of this diagram are shown in Figure 4. The diagram is organized according to biology’s central dogma, showing DNA being transcribed to RNA, and RNA being translated to protein. Regulation can occur at any stage along that path. At this level of detail, individual binding sites are not shown. Rather, activation or inhibition arrows are drawn pointing from transcription factors and their ligands to an icon representing RNA polymerase binding to the DNA strand. Attenuation regulators point to either a full-length or truncated mRNA strand. Translational regulators are shown binding to the mRNA strand and activating or inhibiting an icon representing the ribosome and translation. If the resulting polypeptide forms one or more complexes or participates in a reaction (such as a post- translational modification or sequestration interaction), the complexes or modified forms are also shown, along with any enzymes, activators or inhibitors that control the reaction. Finally, if some form of the protein has enzymatic activity, then its substrate-level activators or inhibitors are shown with arrows pointing to the enzyme. Mousing over any element of the diagram pops up a tooltip containing additional details or explanation.


Regulatory network operations in the Pathway Tools software.

Paley SM, Latendresse M, Karp PD - BMC Bioinformatics (2012)

Sample regulation summary diagrams for E. coli . a) The trpD diagram shows inhibition by TrpR (a homodimer, as indicated by the appearance of multiple stacked copies) bound to tryptophan, attenuation by tryptophanyl-tRNA, and substrate-level regulation of the final complex by tryptophan. b) The oppD diagram shows inhibition by several transcription factors (the leucine ligand blocks regulation by Lrp), and regulation of translation by a spermidine riboswitch and RNA GcvB with accessory protein Hfq (a homosexamer). c) The glnG diagram shows activation and dual regulation by several transcription factors, and post-translational modification triggered by phosphorylated NtrB.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3473263&req=5

Figure 4: Sample regulation summary diagrams for E. coli . a) The trpD diagram shows inhibition by TrpR (a homodimer, as indicated by the appearance of multiple stacked copies) bound to tryptophan, attenuation by tryptophanyl-tRNA, and substrate-level regulation of the final complex by tryptophan. b) The oppD diagram shows inhibition by several transcription factors (the leucine ligand blocks regulation by Lrp), and regulation of translation by a spermidine riboswitch and RNA GcvB with accessory protein Hfq (a homosexamer). c) The glnG diagram shows activation and dual regulation by several transcription factors, and post-translational modification triggered by phosphorylated NtrB.
Mentions: The Regulation Summary Diagram provides a compact and information-rich overview of all the direct regulatory influences on a single gene product, from transcription and translation to post-translational modifications and substrate-level modulation. Some examples of this diagram are shown in Figure 4. The diagram is organized according to biology’s central dogma, showing DNA being transcribed to RNA, and RNA being translated to protein. Regulation can occur at any stage along that path. At this level of detail, individual binding sites are not shown. Rather, activation or inhibition arrows are drawn pointing from transcription factors and their ligands to an icon representing RNA polymerase binding to the DNA strand. Attenuation regulators point to either a full-length or truncated mRNA strand. Translational regulators are shown binding to the mRNA strand and activating or inhibiting an icon representing the ribosome and translation. If the resulting polypeptide forms one or more complexes or participates in a reaction (such as a post- translational modification or sequestration interaction), the complexes or modified forms are also shown, along with any enzymes, activators or inhibitors that control the reaction. Finally, if some form of the protein has enzymatic activity, then its substrate-level activators or inhibitors are shown with arrows pointing to the enzyme. Mousing over any element of the diagram pops up a tooltip containing additional details or explanation.

Bottom Line: We introduce a novel type of enrichment analysis that asks whether a gene-expression dataset is over-represented for known regulators.We present algorithms for ranking the degree of regulatory influence of genes, and for computing the net positive and negative regulatory influences on a gene.Pathway Tools provides a comprehensive environment for manipulating molecular regulatory interactions that integrates regulatory data with an organism's genome and metabolic network.

View Article: PubMed Central - HTML - PubMed

Affiliation: Bioinformatics Research Group, SRI International 333 Ravenswood Ave, Menlo Park, CA 94025, USA.

ABSTRACT

Background: Biologists are elucidating complex collections of genetic regulatory data for multiple organisms. Software is needed for such regulatory network data.

Results: The Pathway Tools software supports storage and manipulation of regulatory information through a variety of strategies. The Pathway Tools regulation ontology captures transcriptional and translational regulation, substrate-level regulation of enzyme activity, post-translational modifications, and regulatory pathways. Regulatory visualizations include a novel diagram that summarizes all regulatory influences on a gene; a transcription-unit diagram, and an interactive visualization of a full transcriptional regulatory network that can be painted with gene expression data to probe correlations between gene expression and regulatory mechanisms. We introduce a novel type of enrichment analysis that asks whether a gene-expression dataset is over-represented for known regulators. We present algorithms for ranking the degree of regulatory influence of genes, and for computing the net positive and negative regulatory influences on a gene.

Conclusions: Pathway Tools provides a comprehensive environment for manipulating molecular regulatory interactions that integrates regulatory data with an organism's genome and metabolic network. Curated collections of regulatory data authored using Pathway Tools are available for Escherichia coli, Bacillus subtilis, and Shewanella oneidensis.

Show MeSH
Related in: MedlinePlus