From specific gene regulation to genomic networks:

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From specific gene regulation to genomic networks

• A global analysis of transcriptional regulation
  in Escherichia coli
• Thieffry, Huerta, Perez-Rueda, Collado-Vides

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Outline

• Background
• Goals
• Results
• Connectivity
• Structure
• Conclusions
• Discussion

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Background

• RegulonDB database of E. coli transcriptional
  regulation collated from the experimental
  literature
• 500 regulatory mechanisms
• 100 regulatory proteins
• 300 promoters
• Note Collado-Vides is collaborator of Peter Karp

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Goals

• Global properties of transcriptional network in
  E. coli
• Connectivity
• Number of regulators per gene
• Number of genes per regulator
• Mean connectivity of entire network
• Feedback circuits
• Types
• Numbers

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How is connectivity computed?
Fig. 1
connectivity vs. architecture
Connectivity
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Genetic regulatory network
Regulated gene
Regulatory gene
Regulated gene
Regulated Regulatory gene
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Fig. 2
CRP
sodA
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Connectivity

• A given txn factor regulates on average 3 genes
• A given gene is controlled by 2 txn factors

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Operon
DNA
genA
genB
genC
RNA
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Fig. 2
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Fig. 1
Structure
hierarchical regulatory tree
intertwined feedback circuits
independent small regulatory modules
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Questions

• How many regulatory feedback circuits are found
  in the E. coli txnal network?
• What is their average length?
• What fraction is positive and what fraction is
  negative?
• How are they interconnected?
• ? Note limited to txnal regulation only

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Network digression

• Degree of clustering given two nodes A and B
  that are both connected to C, what is the
  probability that A and B are also connected?
• Average distance between two nodes
• Size of isolated subgraphs

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Matrix

• 96 transcriptional regulators
• 55 of these regulate regulators
  (interregulation)
• Columns all genes controlled by same protein
• Rows all regulators of a given gene
• 2 element circuits pairs symmetric to diagonal

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Results

• Mostly autoregulatory, inhibitory (diagonal) 87
• CRP (cAMP receptor protein, activated in the
  absence of glucose) regulates many other
  regulators
• Little cross-regulation at txnal level
• Positive autoregulators GutM, PhoB, RhaR 6.5
• /- Ada, CRP, NR(I) 6.5

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Conclusions

• Prominence of 1-element regulatory circuits
• Small subnetworks, loosely interconnected
• Modular organization

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Discussion

• Negative autoregulation promotes homeostasis
• Its cheaper, too
• Positive circuits ? differentiation(switches)

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Switches / positive circuits

• CRP responds to absence of glucose
• NR(I) regulates nitrogen metabolism
• PhoB involved with phosphate transport and
  regulation
• Ada induces DNA-repair system
• Few positive circuits because most require
  metabolite control (i.e. more than
  transcriptional control)

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Robustness

• 4000 genes, 1000 functionally characterized, 500
  in database, 100 regulatory proteins in database
• Assume 110 ratio regulatory to regulated genes
• ¼ of network estimated to be represented
• How much are results influenced by historical
  bias? i.e. researchers dont expect more than 2
  or 3 regulators per gene, so they dont look for
  more, or types of regulation discovered are
  limited by techniques

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Not considered

• Protein-protein interactions
• Signalling cascades
• Metabolite repression/activation
• Post-transcriptional regulation

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More discussion

• Probably a good estimate of connectivity and
  architecture, taking these limitations into
  consideration
• Structural limitations on number of regulators
  (s70 requires proximity and direct contact)
• Further theoretical reading work of Stuart
  Kauffman and Michael Savageau

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THE END