The Challenge of Understanding Specificity in Bio-molecular Networks

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The Challenge of Understanding Specificity in
Bio-molecular Networks

• Anirvan M. Sengupta
• Physics Dept./ BioMaPS Inst.
• Rutgers University

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A Corner of the Molecular Jungle
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BiologyLots of Rube Golberg Machines Melded into
One?
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Questions Information Flow, Specificity and
Robustness

• How does such sytems function robustly?
• How come crosstalk does not become interference?
• Design principles or frozen accidents?

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Lock and Key Specificity

• Specificity of substrate recognition built into
  enzymes.
• Each pathway has dedicated extremely specific
  enzymes.
• Often not true for eukaryotic systems.

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Things to Understand Quantitatively

• Constraints on graded affinity
• Network effects in the signaling system
• Combinatorial control of promoters
• Genetic networks with complex promoters
• Commitment to cell fates

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Evolution of Regulatory Elements and
Bioinformatics

• Affinity is graded and number targets decided by
  concentration.
• Evolutionary model says more pleiotropic -gtless
  specific (Sengupta, Djordjevic, Shraiman, PNAS,
  2002).
• Improved bioinformatics for E. Coli TFs
  (Djordjevic, Sengupta, Shraiman, Genome Research,
  2003, in press)

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Yeast Life Cycle
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Yeast MAPK Conundrum

• Mating and filamentation governed by same
  pathway.
• No scaffold found so far
• Could the strength/pattern of excitation be the
  casue?

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Combinatorial Control of Yeast Mating Type
Identity

• Combinatorial control by three regulated factors
  (and a constitutive one) regulate cell type
  identity.
• Detection of direct targets by combining sequence
  analysis and microarray data (OFlanagan,
  Nagaraj, Mathias, Vershon, Sengupta, in
  preparation)

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Dorso-ventral Patterning in Fly Embryo

• Morphogen gradient Nuclearized dorsal.
• Different cell fates along the axis.

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Dorsal Ventral Patterning Network

• How does the gradient of dorsal get read into
  different cell fates?
• Transcriptional cascade involving twist and
  snail.

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Gradients and Differential Expression
High levels of dorsal TF Ventral Drosophila
embryo cells
Low levels of dorsal TF Lateral Drosophila embryo
cells
Low dorsal concentrations mean that only the high
affinity sites in the rhomboid promoter are able
to bind dorsal. Since neither Twist nor snail are
expressed, rhomboid can be transcribed
At high dorsal concentrations, low affinity
binding sites permit transcription of Twist which
in turn activates transcription of snail. Snail
inhibits rhomboid transcription
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Conclusion

• Understanding quantitative models of specificity
  is going to become more and more important.
• We need to combine biophysics, dynamical modeling
  and bioinformatics together for that purpose.