The Challenge of Understanding
Specificity in Bio-molecular
Networks
Anirvan M. Sengupta
Physics Dept./ BioMaPS Inst.
Rutgers University
A Corner of the Molecular Jungle
Biology=Lots of Rube Golberg
Machines Melded into One?
Questions: Information Flow,
Specificity and Robustness
• How does such sytems
function robustly?
• How come crosstalk
does not become
interference?
• Design principles or
frozen accidents?
Lock and Key Specificity
• Specificity of substrate
recognition built into
enzymes.
• Each pathway has
dedicated extremely
specific enzymes.
• Often not true for
eukaryotic systems.
Things to Understand
“Quantitatively”
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Constraints on graded affinity
Network effects in the signaling system
Combinatorial control of promoters
Genetic networks with complex promoters
Commitment to cell fates
Evolution of Regulatory
Elements and Bioinformatics
• Affinity is graded and number targets decided by
concentration.
• Evolutionary model says more pleiotropic ->less specific
(Sengupta, Djordjevic, Shraiman, PNAS, 2002).
• Improved bioinformatics for E. Coli TFs (Djordjevic,
Sengupta, Shraiman, Genome Research, 2003, in press)
Yeast Life Cycle
Yeast MAPK Conundrum
• Mating and
filamentation
governed by
same pathway.
• No scaffold
found so far
• Could the
strength/pattern
of excitation be
the casue?
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 (O’Flanagan,
Nagaraj, Mathias,
Vershon, Sengupta, in
preparation)
Dorso-ventral Patterning in Fly
Embryo
• Morphogen gradient: Nuclearized dorsal.
• Different cell fates along the axis.
Dorsal Ventral Patterning
Network
• How does the gradient
of dorsal get read into
different cell fates?
• Transcriptional
cascade involving
twist and snail.
Gradients and Differential Expression
High levels of dorsal TF
Ventral Drosophila embryo cells
Low levels of dorsal TF
Lateral Drosophila embryo cells
Twist
Twist
snail
snail
rhomboid
At high dorsal concentrations, low affinity
binding sites permit transcription of Twist which
in turn activates transcription of snail. Snail
inhibits rhomboid transcription
Dorsal
rhomboid
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
High-affinity dorsal binding site
Low-affinity dorsal binding site
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.