Modeling promoter search by E.coli RNA
polymerase : One-dimensional diffusion in
a sequence-dependent energy landscape
Journal of Theoretical Biology 2009
Outline
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Introduction
Previous Work
Preliminary
Materials and Method
Experiment Results
Discussion
Introduction
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Gene Transcription: DNA → RNA
Introduction
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Stages of transcription:
RNA polymerase
binding
release
,
5’
3’
mRNA
Outline
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Introduction
Previous Work
Preliminary
Materials and Method
Experiment Results
Discussion
Previous Work
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1970:
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1981:
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association rate much higher than the rate
achievable by 3D diffusion.
theory for 3D diffusion bind to DNA and then 1D
diffusion on DNA(1D random walk)
1989:
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Two mode(search/recognition) of RNAP binding
to DNA
Previous Work
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1999:
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2005:
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RNAP searches its target site (the promoter) by
randomly binding the DNA and subsequently sliding
along (1D Brownian motion )DNA
same probability(forward/backward) for 1D random
walk is inefficient process
But, a detailed understanding of onedimensional diffusion and the possible
sliding length could not yet be obtained.
Previous Work
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Two kinds of sliding:
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1D Brownian motion random walk
sequence-dependent random walk
sliding
hopping
Intersegment transfer
Three Commonly discussed microscopic pathways for transferring a protein from one
site to another.
Outline
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Introduction
Previous Work
Preliminary
Materials and Method
Experiment Results
Discussion
Preliminary
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assumption :
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the sliding process has a sequence-dependent
component
it does not perform a random walk with equal
probabilities of stepping forward or backward
the sliding is influenced by the binding energy at
each position
Preliminary
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transition rates :
β=(kBT)-1
v affective attempt frequency
kB the Boltzmann constant
T the ambient temperature in Kelvin
Preliminary
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Binding energy E(ip) between the sigma
factor and a promoter p at position ip :
Preliminary
Preliminary
Outline
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Introduction
Previous Work
Preliminary
Materials and Method
Experiment Results
Discussion
Materials and Method
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Weight Matrix W
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the contribution of the 12 nucleotides in the
promoter regions to the binding energy
Materials and Method
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Weight Matrix W
Color scheme: Black=A , dark gray=C, light gray=G, white=T.
Materials and Method
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The binding energy E(i) at position i of an
analyzed DNA sequence is obtained by
minimizing the energy score calculated
according to Eq.
high negative overall energies should indicate candidate
target sites
Outline
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Introduction
Previous Work
Preliminary
Materials and Method
Experiment Results
Discussion
Experiment Results
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Data:
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σ70 and 651 promoters from RegulonDB
Average energy landscape E(i)
Experiment Results
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Speed of sliding :
(τi denotes the time the protein spends bound to site i )
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Region 1: |g|=0 → ri = 2v.
Region 2: |g|>0 → ri < 2v.
Region 3: |g|>0 → ri < 2v.
Region 4: |g|=0 → ri = 2v.
Experiment Results
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Direction of sliding :
(pi means forward ; qi means backward)
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Experiment Results
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Efficiency of promoter search :
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Mean first-passage time(MFPT)
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The mean number of steps the protein will make to
slide from site i = 0 to site i = L
(αi=qi/pi)
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Assuming α0 = α1 = ….αk
( the approximation is a polynomial of order L depending on α )
Experiment Results
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Efficiency of promoter search :
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L=50 (αi=qi/pi)
Experiment Results
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Efficiency of promoter search :
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L=-50 (αi=qi/pi)
Experiment Results
Outline
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Introduction
Previous Work
Preliminary
Materials and Method
Experiment Results
Discussion
Discussion
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RNAP can move either direction
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L=50(5’→ 3’),in Region 2:
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MFPT decrease =more efficient
L=-50(3’→ 5’),in Region 3:
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MFPT decrease =more efficient
Discussion
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The decrease of binding energies the RNAP
faces when approaching the promoters
strongly influences the efficiency of promoter
search.
Discussion
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Summary
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the movement of the RNAP along the DNA slows
down when approaching the promoter regions.
sequence-dependent interaction between σ and
promoter surrounding directs the RNAP towards
the promoter.
mean first-passage time decreases when
approaching the promoter regions
(promoter search becomes more efficient in this region)
Discussion
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surrounding of the promoters contains
important information to guide the RNAP
and its sigma subunit.
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increasing the probability of transcription
initiation by :
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slowing down the sliding process
controlling the direction
more efficiency of the movement.
Problem
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Why like poisson?
Do other species have
the same distribution?
Do all promoters have familiar energy
landscape surrounding of the promoters?