??? His Central Dogma: DNA is a Read-Only-Memory. Who manages the - - PowerPoint PPT Presentation
At ; June 19, 2007 Novel Hypothesis on the Self-Regulation of Genetic Information: Scenario from One-Dimensional DNA into Spatio-Temporal Order Protein Conclusion: The concept of network is insufficint.
Novel Hypothesis on the Self-Regulation of Genetic Information: Scenario from One-Dimensional DNA into Spatio-Temporal Order
Central Dogma: “DNA is a Read-Only-Memory.”
At 桂林; June 19, 2007
Arg His
Cell
ProteinConclusion: The concept of
“network” is insufficint. What is necessary for additional?
京都大学 吉川研一
Current network hypothesis gives the answer:
Hypothesis of Jacob & Monod (1961)
Who manages the expression of 20,000 genes?
how? Absence of CPU.
switching on hundreds of senes.
Difficulty of simultaneous switching on many genes.
diminishes the stability of the fix points in the network: Difficulty of robust on/off switching.
Effect of cross-talk
We should think of something else!
AFM Microscopy
Broadening with Gaussian (～300 nm)
1.5μｍ 1.5μｍ 1.5μｍ Fluorescence Microscopy
Yoshinaga, et al., J.Chem.Phy.2002.
T4DNA: 155 kbp
Persistence Length; 50 nm (170 base pairs) Short DNA is a stiff rod.
DNA above several kilo base pairs is “giant”. All of the genomic DNAs are giant (above 1 mm).
Helix-Coil Transition Coil-Globule Transition
Melting Transition of Double Stranded DNA Folding Transition of Giant DNA
Continuous Transition On/Off Transition
Coil （Unfolded) Rc ~ λN 3/5
Large Change in Density
Ratio on the Density
When N = 100 (30kbp), λ= 100nm, s = 4nm2
ρg/ρc ~ Rc
３/Rｇ ３ ~ 105
Globule （Folded) Rg ~ (λsN) 1/3
Globule Coil N: Number of segments λ: Kuhn length s: Cross section of segment
Continuous or Discrete?
Most Experimental Studies Reported As Continuous
Monomolecular Condensation of λ-DNA Induced by Cobalt Hexammine
In Abstract: "Some interesting properties of monomolecular condensation are noted. (1) The transition is not a two-state reaction, as judged by measurements of the diffusion coefficient through the transition zone. (2) The transition for monomolecular condenstation is diffuse. ‥‥‥‥"
R R
Condensing Chemical
Current concept
T4DNA(166kbp) Contour length:57μm
Discrete: Single chain Continuous: Ensemble of chains
Folding transition induced by spermine (4+)
See e.g.; JCP,102,6595(’95); PRL, 76,3029(’96); JPCB, 101, 9396 (‘97).
Observation on Single DNA Molecules
density Free Energy
1
10 ~ n
Always Continuous
2
10 ~ n
First-Order Phase Transition Liquid Solid
N=100 corresponds to DNA with 30kbp, where Kuhn length is 100nm (300bp)
Experiment
Matsuzawa, et al., JACS(’96)
Nucleation & Growth in a Single Chain
Time Interval : 2s
10μm
Single DNA Observation (T4DNA: 57μm)
Simulation
Sakaue, et al., JCP(’02)
RNA pH ATP
high low high low Alkaline Acid
Recognition of specific base-sequences on DNA by individual regulatory factors.
Variable: Finite number (discrete; the density of “N”)
Nonspecific abundant chemicals such as ATP; Na,K-ions; RNA; pH; etc.
Environmental species: Large number (concentration is almost given by the density of “R”)
Makita, et al., FEBS Letters, 460 (1999)
“Environment” causes on/off switching.
Luckel, Tsumoto, et al., Biophys. Chem.(2003).
Compaction of DNA completely inhibits the transcriptional activity of genes
不連続転移は、100 kbp 以上の領域 (10 ～ 100 以上の 遺伝子を含む)で初めて起こる。
DNA mRNA DNA
Yamada et al., APL, 2005
Coil state ⇒ Transcriptional activity ON Globule state ⇒ Transcriptional activity OFF I n the region larger than 100 kbp (more than 10 ～ 100 genes), discrete transition occurs.
Switching of the Transcriptional Activity is Caused by the changa
Biomacromol.(2003)
Giant DNA Short DNA
Shindo, et al., J.Biotech.(2007).
Summary on Genetic Regulation
1) Environmental parameters induce On/Off switching on the conformation of giant DNA. 2) The correlation length in intra-chain segregation is determined by the cross-talk between DNA and environment. 3) On/Off switching of gene expression is driven by the conformational transition of giant DNA. 4) Network hypothesis may stand for the soft control of gene expression. Robust control will be managed by the conformational transition in giant DNA.
Outer Environment
Metabolic Network
Loose Packing
Intra-cellular Network Genetic Regulators
Expression
Transcription Nuclear Environment Folder of genes Tight Packing Unfolded DNA
Network: Fluctuating pairs of key-locks Environment: Robust owe to large number
Life is a hybrid system between network and environment.
1) Selective on/off switching on a large number of genes Cell Differentiation, Cancer, AIDS, etc. 2) Construction of the own body Turing Pattern, Apoptosis, etc.
４. Reaction-Diffusion System (Turing Pattern)
１．Positioning
２. Cell automaton
２．Cell Automaton
３. Neighboring Interaction
３．Neighboring Interaction
∂u ∂t = γf u,v
( )+ ∇
2u,∂v ∂t = γg u,v
( )+ d∇
2vf u, v
( ) = a − u − h u,v ( ), g u,v ( ) = α b − v ( )− h u,v ( )
h u,v
( ) =
ρuv 1 + u + Ku
2 Tail Head
Mouse Zebrafish Periodicity: 90-120min Periodicity: 30min
⎪ ⎪ ⎪ ⎩ ⎪ ⎪ ⎪ ⎨ ⎧ − + + − = + + + − = ∇ + − + − = z k x k xz k z k x k y k y x D x k y k xz k x
8 2 7 1 6 2 5 4 2 3 2 1
1 1 & & &
x: Hes1 protein y: hes1 mRNA z: E2A(?) protein
Somite Segmentation is Generated through Traveling Waves
Experiment Numerical
Oscillation is robust.
Oscillation of Hes-1 Ensemble of Cells Individual Cells
Fluctuating rhythm
Numerical Example
Isolated Cells 1-D Couples Cells
1) Selective on/off switching on a large number of genes Cell Differentiation, Cancer, AIDS, etc. 2) Construction of the own body Turing Pattern, Apoptosis, etc. Nonlinear dynamics under far- from-equilibrium conditions
Fusion between Physico-Mathmatics and Bioscience will open the next era.
20th Century: Accumulation of the knowledge on Elements.
21th Century: Understanding of System Dynamics.
馬 劉
Research Colleagues at Kyoto Univ.