complexity of chromatin folding is captured by the strings...
TRANSCRIPT
![Page 1: Complexity of chromatin folding is captured by the strings ...ibi.hzau.edu.cn/bgma/sysbio/stuPDF/2012-19.pdf · SBS mode analysis strongly supports the conclusion that the principles](https://reader033.vdocuments.net/reader033/viewer/2022051605/600f0638caf9b8078a3e2123/html5/thumbnails/1.jpg)
Complexity of chromatin folding is
captured by the strings and binders
switch model
王文韬 周群丰
![Page 2: Complexity of chromatin folding is captured by the strings ...ibi.hzau.edu.cn/bgma/sysbio/stuPDF/2012-19.pdf · SBS mode analysis strongly supports the conclusion that the principles](https://reader033.vdocuments.net/reader033/viewer/2022051605/600f0638caf9b8078a3e2123/html5/thumbnails/2.jpg)
KEY?
![Page 3: Complexity of chromatin folding is captured by the strings ...ibi.hzau.edu.cn/bgma/sysbio/stuPDF/2012-19.pdf · SBS mode analysis strongly supports the conclusion that the principles](https://reader033.vdocuments.net/reader033/viewer/2022051605/600f0638caf9b8078a3e2123/html5/thumbnails/3.jpg)
chromosome compaction
Chromosome
compaction
mitotic cycle
dynamic
compaction
Hetero- and
eu-chromosome
Compaction
(stable territories)
Interphase
dynamic compaction
(discrete territories )
![Page 4: Complexity of chromatin folding is captured by the strings ...ibi.hzau.edu.cn/bgma/sysbio/stuPDF/2012-19.pdf · SBS mode analysis strongly supports the conclusion that the principles](https://reader033.vdocuments.net/reader033/viewer/2022051605/600f0638caf9b8078a3e2123/html5/thumbnails/4.jpg)
mitotic cycle dynamic compaction
unfoldingcompaction
![Page 5: Complexity of chromatin folding is captured by the strings ...ibi.hzau.edu.cn/bgma/sysbio/stuPDF/2012-19.pdf · SBS mode analysis strongly supports the conclusion that the principles](https://reader033.vdocuments.net/reader033/viewer/2022051605/600f0638caf9b8078a3e2123/html5/thumbnails/5.jpg)
Hetero-chromomatin and euchromamtin
----stable compaction
![Page 6: Complexity of chromatin folding is captured by the strings ...ibi.hzau.edu.cn/bgma/sysbio/stuPDF/2012-19.pdf · SBS mode analysis strongly supports the conclusion that the principles](https://reader033.vdocuments.net/reader033/viewer/2022051605/600f0638caf9b8078a3e2123/html5/thumbnails/6.jpg)
• In inter-phrase , highly coordinated
cellular processes such astranscription,
DNA repair, and replication take place,
creating cell-type–specific chromatin
folding .
giving rise to giving rise to discrete
chromosome territories.
Grigoryev et al.2009
![Page 7: Complexity of chromatin folding is captured by the strings ...ibi.hzau.edu.cn/bgma/sysbio/stuPDF/2012-19.pdf · SBS mode analysis strongly supports the conclusion that the principles](https://reader033.vdocuments.net/reader033/viewer/2022051605/600f0638caf9b8078a3e2123/html5/thumbnails/7.jpg)
●Spatial genome organization is guided by
intra-and inter -chromosomal interactions
mediated by nuclear components that
include transcription factors, transcription
and replication factories, Polycomb bodies,
and contacts with the lamina.
![Page 8: Complexity of chromatin folding is captured by the strings ...ibi.hzau.edu.cn/bgma/sysbio/stuPDF/2012-19.pdf · SBS mode analysis strongly supports the conclusion that the principles](https://reader033.vdocuments.net/reader033/viewer/2022051605/600f0638caf9b8078a3e2123/html5/thumbnails/8.jpg)
How binding of diffusible factors to specific genomic regions drives chromatin folding remains poorly understood.
?
![Page 9: Complexity of chromatin folding is captured by the strings ...ibi.hzau.edu.cn/bgma/sysbio/stuPDF/2012-19.pdf · SBS mode analysis strongly supports the conclusion that the principles](https://reader033.vdocuments.net/reader033/viewer/2022051605/600f0638caf9b8078a3e2123/html5/thumbnails/9.jpg)
Three key tech. to analysis
compaction
FISH: Imaging of single loci
3C (chromosome conformation
capture approaches): genome-wide
mapping of chromatin interactions
Hi-C(A global analysis of genome-
wide 3C)
![Page 10: Complexity of chromatin folding is captured by the strings ...ibi.hzau.edu.cn/bgma/sysbio/stuPDF/2012-19.pdf · SBS mode analysis strongly supports the conclusion that the principles](https://reader033.vdocuments.net/reader033/viewer/2022051605/600f0638caf9b8078a3e2123/html5/thumbnails/10.jpg)
From FISH :R2 can be measured
R² :chromatin folding is often measured by the mean-square spatial distance
S:two genomic regions as a function of their linear genomic
V: scaling exponent
R²(s)~s2v:exhibits scaling properties
From HI-C :Pc(s) can be estimated
PC(S): contact probability, how frequently two loci contact each other as a function
of s.
α:an exponent depend on Cm
Pc(s)~1/Sα:relationship between Pc and S
![Page 11: Complexity of chromatin folding is captured by the strings ...ibi.hzau.edu.cn/bgma/sysbio/stuPDF/2012-19.pdf · SBS mode analysis strongly supports the conclusion that the principles](https://reader033.vdocuments.net/reader033/viewer/2022051605/600f0638caf9b8078a3e2123/html5/thumbnails/11.jpg)
Reason for exploring SBS mode
• FG mode describe that an average exponent α ~ 1.08,
at genomic distances 0.5–7 Mb.The observation of αof
approximately 1.08 has led to the suggestion that
chromatin behavior could be explained by a single
folding structure. But recent applications of Hi-C have
found a lower exponent αin Drosophila and revealed
differing contact frequencies in human cells according to
chromatin expression status .The observation that the
exponent α may not be universal or conserved
![Page 12: Complexity of chromatin folding is captured by the strings ...ibi.hzau.edu.cn/bgma/sysbio/stuPDF/2012-19.pdf · SBS mode analysis strongly supports the conclusion that the principles](https://reader033.vdocuments.net/reader033/viewer/2022051605/600f0638caf9b8078a3e2123/html5/thumbnails/12.jpg)
![Page 13: Complexity of chromatin folding is captured by the strings ...ibi.hzau.edu.cn/bgma/sysbio/stuPDF/2012-19.pdf · SBS mode analysis strongly supports the conclusion that the principles](https://reader033.vdocuments.net/reader033/viewer/2022051605/600f0638caf9b8078a3e2123/html5/thumbnails/13.jpg)
SBS mode
• In “strings and binders switch” (SBS) mode, nonrandom chromatin
conformations are established through attachment of diffusible
factors (binders) to binding sites. Binder-mediated interactions
give rise to a variety of stable chromatin architectures that can
coexist in the nucleus. Chromatin folding changes in response to
changes in binding site distribution, binder concentration, or
binding affinity, in a switch-like fashion across specific threshold
values via thermodynamics mechanisms
• More importantly, SBS model describes in a single framework all current experimental data on chromosome architecture from FISH, Hi-C and 3C approaches
![Page 14: Complexity of chromatin folding is captured by the strings ...ibi.hzau.edu.cn/bgma/sysbio/stuPDF/2012-19.pdf · SBS mode analysis strongly supports the conclusion that the principles](https://reader033.vdocuments.net/reader033/viewer/2022051605/600f0638caf9b8078a3e2123/html5/thumbnails/14.jpg)
• SBS mode evaluated the dynamics and equilibrium properties of
the polymer using extensive Monte Carlo (MC) simulations in the
known range of the biochemical values of Cm(concentration of
binders ) and EX.( binders affinity to polymer site)
• EX=2KBT ( kB is the Boltzmann constant and T is the temperature
• in kelvin)
Ex change with the Cm
• Ctr (threshold concentration)
![Page 15: Complexity of chromatin folding is captured by the strings ...ibi.hzau.edu.cn/bgma/sysbio/stuPDF/2012-19.pdf · SBS mode analysis strongly supports the conclusion that the principles](https://reader033.vdocuments.net/reader033/viewer/2022051605/600f0638caf9b8078a3e2123/html5/thumbnails/15.jpg)
In the SBS model, the shape of the
two functions R2(s) and Pc(s) is
sensitive to the concentration of
binding molecules, Cm
Cm & Ctr
R²(s)~S2v
Pc(s)~1/Sα
![Page 16: Complexity of chromatin folding is captured by the strings ...ibi.hzau.edu.cn/bgma/sysbio/stuPDF/2012-19.pdf · SBS mode analysis strongly supports the conclusion that the principles](https://reader033.vdocuments.net/reader033/viewer/2022051605/600f0638caf9b8078a3e2123/html5/thumbnails/16.jpg)
Comparison of the SBS and Other Models Against
Experimental Data
Taken together:
1.Experiments strongly argue chromatin have no
general α ,different cell ,different chromosoms (even in same cell )
different stage (even same chromosome) have different α.
2.SBS model has the power to explain the whole range of α
exponents identified experimentally
3.The so –called general α may help explain specific transitional
states for some genomic regions, as, for instance, rapid chromatin
decondensation and chromatin looping out of chromosome
territories during gene activation.
![Page 17: Complexity of chromatin folding is captured by the strings ...ibi.hzau.edu.cn/bgma/sysbio/stuPDF/2012-19.pdf · SBS mode analysis strongly supports the conclusion that the principles](https://reader033.vdocuments.net/reader033/viewer/2022051605/600f0638caf9b8078a3e2123/html5/thumbnails/17.jpg)
The SBS Model Reproduces the Organization of
Chromatin in Topological Domains.
![Page 18: Complexity of chromatin folding is captured by the strings ...ibi.hzau.edu.cn/bgma/sysbio/stuPDF/2012-19.pdf · SBS mode analysis strongly supports the conclusion that the principles](https://reader033.vdocuments.net/reader033/viewer/2022051605/600f0638caf9b8078a3e2123/html5/thumbnails/18.jpg)
changed the state of three contiguous sites from binding
the red binders to no longer having affinity to binders
![Page 19: Complexity of chromatin folding is captured by the strings ...ibi.hzau.edu.cn/bgma/sysbio/stuPDF/2012-19.pdf · SBS mode analysis strongly supports the conclusion that the principles](https://reader033.vdocuments.net/reader033/viewer/2022051605/600f0638caf9b8078a3e2123/html5/thumbnails/19.jpg)
The SBS Model Reproduces the Dynamic Folding
Behaviors of Chromatin.
• As a final test to the power of the SBS model, researcher
investigated the kurtosis K =(R4(s))∕(R2(s))2, which is the ratio of the
fourth and second moment of the spatial distance.
K=1.5,corresponding is
compact and open
K=5,corresponding
region is transition
K carry information of
genomic locus and cell –
cell variation ,and depend
on Cm
indeed, chromatin exists in a complex
mixture that includes fractal as well as
open and closed states
![Page 20: Complexity of chromatin folding is captured by the strings ...ibi.hzau.edu.cn/bgma/sysbio/stuPDF/2012-19.pdf · SBS mode analysis strongly supports the conclusion that the principles](https://reader033.vdocuments.net/reader033/viewer/2022051605/600f0638caf9b8078a3e2123/html5/thumbnails/20.jpg)
Discussion
• 1. Interphase nuclei exhibit dynamic chromatin structures that change in response to cellular signals and influence patterns of gene expression. 2 . genomic architectures sharp regulation of nuclear architecture can be obtained reliably by simple strategies, such as protein up-regulation or modification, without the need to fine tune these specific parameters.
• 3. SBS mode analysis strongly supports the conclusion that the principles of chromatin folding in interphase nuclei cannot be recapitulated by a single “universal” conformational state (and its given α).4. SBS model illustrates key physical concepts and basic required ingredients to explain chromatin folding in a variety of states identified in living systems, a variety of specific binding factors exist, where different regions can spontaneously fold into different chromatin states
• 5. polymer scaling theory ensures that the exponents in R2 and Pc are independent of the minute details of the system considered and reflect universal properties
• 6The thermodynamic mechanisms discussed, which are robust and independent of specific molecular details, will be relevant to many cellular and nuclear processes requiring spatial organization7.SBS mode is a powerful mode to analysis chromatin structure organization.
![Page 21: Complexity of chromatin folding is captured by the strings ...ibi.hzau.edu.cn/bgma/sysbio/stuPDF/2012-19.pdf · SBS mode analysis strongly supports the conclusion that the principles](https://reader033.vdocuments.net/reader033/viewer/2022051605/600f0638caf9b8078a3e2123/html5/thumbnails/21.jpg)
![Page 22: Complexity of chromatin folding is captured by the strings ...ibi.hzau.edu.cn/bgma/sysbio/stuPDF/2012-19.pdf · SBS mode analysis strongly supports the conclusion that the principles](https://reader033.vdocuments.net/reader033/viewer/2022051605/600f0638caf9b8078a3e2123/html5/thumbnails/22.jpg)
• Shopland et al. 2006
![Page 23: Complexity of chromatin folding is captured by the strings ...ibi.hzau.edu.cn/bgma/sysbio/stuPDF/2012-19.pdf · SBS mode analysis strongly supports the conclusion that the principles](https://reader033.vdocuments.net/reader033/viewer/2022051605/600f0638caf9b8078a3e2123/html5/thumbnails/23.jpg)