The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq...

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The Physics of Chromosomes: Loops and Entropy, that's what it's all about Dieter W. Heermann Heidelberg University

Transcript of The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq...

Page 1: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

The Physics of Chromosomes: Loops and Entropy, that's

what it's all aboutDieter W. Heermann

Heidelberg University

Page 2: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

Derive a chromosome model that works across species, across phases, hence that is able to capture the underlying principles of chromosome folding.

Can explain data from various sources simultaneously.

Can predict biological as well as mechanical properties.

Key Problem

Page 3: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

Yes, we can!

Key Problem

Page 4: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

Human chromosomes (interphase and metaphase)

Escherichia coli

Yeast

Key Problem

Page 5: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

How can we obtain information on

the structure?

Page 6: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

Key Experiments: Eukaryotes

Label (for example fluorescence in situ hybridization (FISH)) specific sites along the chromosome.

Page 7: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

Localization microscopy reveals expression-dependent parameters of chromatin nanostructures Manfred Bohn, Philipp Diesinger, Rainer Kaufmann, Yanina Weiland, Patrick Müller, Manuel Gunkel, Alexa von Ketteler, Paul Lemmer, Michael Hausmann, Dieter W. Heermann and Christoph CremerBiophysical Journal, Volume 99, Issue 5, 1358-1367, 8 September 2010

0.9

1

1.1

1.2

1.3

1.4

1.5

1.6

0 50 100 150 200 250 300

g(r)

r [nm]

Fibroblast CellsHeLa cells (strain I)HeLa cells (strain II)

Key Experiments: Eukaryotes

Page 8: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

T.Cremer and C. Cremer, Nature Reviews Genetics vol. 2, no. 4, pp. 292-301 (April, 2001)

Chromosome Territories

Key Experiments: Eukaryotes

Staining of the entire chromosome

Page 9: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

W. de Laat, Current Opinion in Cell Biology 2007, 19:317–320

Key Experiments: Eukaryotes

Page 10: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

Comprehensive Mapping of Long-Range Interactions Reveals Folding Principles of the Human Genome E. Lieberman-Aiden et. al., Science 2010

Key Experiments: Eukaryotes

Page 11: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

Key Experiments

Spatial Information

Measure two, few or many physical positions

Topological Information

Measure contacts without spatial information

Page 12: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

The Model

Page 13: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

coarse grained description

The Model

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Heermann, Heidelberg University, 2015

The Model

Basic assumptions:The backbone of the chain is given by a simple self-avoiding walk.

Page 15: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

A B C

chromosome chromosome chromosome

chro

mos

ome

The effect of loops on the conformation

The Model

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Heermann, Heidelberg University, 2015

The Model

Basic assumptions:The backbone of the chain is given by a simple self-avoiding walk. Two parts of the polymer form loops with a certain probability. Loops are not static but can change in the course of time; their size and position are chosen from a broad range.

Diffusion-Driven Looping Provides a Consistent Framework for Chromatin Organization Manfred Bohn and Dieter W. HeermannPLoS ONE 5(8): e12218. doi:10.1371/journal.pone.0012218 (2010)

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Heermann, Heidelberg University, 2015

Influence of the catenation constraint on elongation and segregation of ring polymers Manfred Bohn, Dieter W. Heermann, Odilon Lourenço, Claudette CordeiroMacromolecules, 43 (5), 2564–2573 (2010)

Topological interactions between ring polymers: Implications for chromatin loops Manfred Bohn and Dieter W. HeermannJ. Chem. Phys. 132, 044904 (2010)

Loops

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Heermann, Heidelberg University, 2015

Loops

0

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0 0.5 1 1.5 2 2.5 3

effective

potentialUring(r)

r/Rg

A B

0.8

0.85

0.9

0.95

1

1.05

0 0.005 0.01 0.015 0.02 0.025 0.03 0.035

exp(�U(0)/N)

1/N

N=64

N=128

N=256

N=384

N=512

N=1024

N=1536

N=2048

Page 19: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

Loops

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potentialUring(r)

r/Rg

A BN=64

N=128

N=256

N=384

N=512

N=1024

N=1536

N=2048So loops repel each other!

Let‘s look at prokaryotes.

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Heermann, Heidelberg University, 2015

e.coli

oriC

ter

I2

C1 C4

D3

C10

E10

F10

A7

D8 E4 G2

B8

B9

D9

A11

A

B

IL05IL06

IL05IL06

IL01

t

IL01

t

Source: Willenbrock and Ussery Genome Biology 2004 5:252 doi:10.1186/gb-2004-5-12-252

Curved DNA

Plectonemic supercoils

Toroidal supercoil

RNA

RNA polymerase

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Heermann, Heidelberg University, 2015

Loops: One More Thing

Transcription Factor Induced DNA Domain Formation Structures the E. coli Chromosome M. Fritsche, S. Li, P. Wiggins and D.W. Heermann, Nucleic Acids Res. 2012 Feb;40(3):972-80.

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Ansatz: Dynamic Loop Model + genes that are co-regulated by a set of same or similar transcription factors, might stay in physical proximity in order to guarantee the efficiency of gene regulation and expression.

Page 22: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

Loops: One More Thing

Transcription Factor Induced DNA Domain Formation Structures the E. coli Chromosome M. Fritsche, S. Li, P. Wiggins and D.W. Heermann, Nucleic Acids Res. 2012 Feb;40(3):972-80.

Page 23: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

e.coliCurved DNA

Plectonemic supercoils

Toroidal supercoil

RNA

RNA polymerase

Looped Star Polymers Show Conformational Transition from Spherical to Flat Toroidal Shapes Pascal Reiß, Miriam Fritsche, and Dieter W. Heermann, Phys. Rev. E 84, 051910 (2011)

Page 24: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

e.coliCurved DNA

Plectonemic supercoils

Toroidal supercoil

RNA

RNA polymerase

Looped Star Polymers Show Conformational Transition from Spherical to Flat Toroidal Shapes Pascal Reiß, Miriam Fritsche, and Dieter W. Heermann, Phys. Rev. E 84, 051910 (2011)

Entropic repulsion between rings leads to an effective bending rigidity.

Page 25: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

Curved DNA

Plectonemic supercoils

Toroidal supercoil

RNA

RNA polymerase

e.coli

Page 26: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

Curved DNA

Plectonemic supercoils

Toroidal supercoil

RNA

RNA polymerase

e.coli

Page 27: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

e.coli

Page 28: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

e.coli

Page 29: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

e.coli

Page 30: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

e.coli

Page 31: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

e.coli

Page 32: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

e.coli

Page 33: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

e.coli

Page 34: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

e.coli

Page 35: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

e.coli

0 0.25 0.5 0.75 10

200

400

600

800

1000

1200

Num

ber o

f Cel

ls

Locus Position (Cell Lengths)

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ter

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0.06

0.08

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0.14

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0 0.2 0.4 0.6 0.8 1Frequency

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lac

Page 36: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

Mo

nte

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ste

ps

Chromosome segregation by the Escherichia coli Min systemBarbara Di Ventura, Benoit Knecht, Helena Andreas, William J. Godinez, Miriam Fritsche, Karl Rohr, Walter Nickel, Dieter W Heermann, Victor Sourjik Molecular Systems Biology 9 Article number: 686 doi:10.1038/msb.2013.44, 2014

0 0.5 10

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4.4 μm 5.6 μm

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e.coli

Page 37: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

entropic forces alone are not sufficient to achieve and maintain full separation of chromosomes

e.coli

Chromosome segregation by the Escherichia coli Min systemBarbara Di Ventura, Benoit Knecht, Helena Andreas, William J. Godinez, Miriam Fritsche, Karl Rohr, Walter Nickel, Dieter W Heermann, Victor Sourjik Molecular Systems Biology 9 Article number: 686 doi:10.1038/msb.2013.44, 2014

Page 38: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

e.coli

0 0.25 0.5 0.75 10

200

400

600

800

1000

1200

Num

ber o

f Cel

ls

Locus Position (Cell Lengths)

oriC C4

ter

lac

A

C

B

10

0 1

1

Long Axis (Cell Lengths)

Shor

t Axi

s

• Assumption of spatial proximity (dynamic loop model + transcriptional network) leads to a „looped-star“.

• Loop structure + entropic repulsion + confinement induces ordering.

• Can explain recent experiments.

Page 39: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

Yeast

Transcriptional Regulatory Network Shapes the Genome Structure of Saccharomyces cerevisiae Songling Li and Dieter W. Heermann, Nucleus. 2013 May-Jun;4(3):216-28

Spindle Pole Body (SPB) loci

rDNA gene cluster

Page 40: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

Yeast

Transcriptional Regulatory Network Shapes the Genome Structure of Saccharomyces cerevisiae Songling Li and Dieter W. Heermann, Nucleus. 2013 May-Jun;4(3):216-28.

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Ansatz: Dynamic Loop Model + genes that are co-regulated by a set of same or similar transcription factors, might stay in physical proximity in order to guarantee the efficiency of gene regulation and expression.

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Heermann, Heidelberg University, 2015

Yeast

Therefore, our approach provided quantitative measurementsand visualizations of subnuclear territories that agree with estab-lished notions of nuclear organization. Themapswere considerablyless accurate and noisier when cell number was reduced to 100(Fig. 2f–j). Similarly, compartmentalization was lost in the absenceof nucleolar alignment (Fig. 2k–o). This underscores the impor-tance ofl arge samples and nuclear landmark alignment, two keyfeatures of our method.

Remodeling of gene territories upon activationTo demonstrate the method’s potential for functional studies ofnuclear organization, we revisited the repositioning of galactosegenes upon transcriptional activation10–12(Fig. 3). We first analyzedthe gene clusterGAL7-GAL10-GAL1 (hereafter referred to asGAL1)and found that in presence of glucose, where the gene is repressed,GAL1 concentrates in a small 0.58mm3 territory close to the nuclearcenter (Fig. 3a), whereas in presence of galactose, whereGAL1 isactive, its territory expands to 0.9mm3 and is enriched near thenuclear periphery (1Dw2-test on signed distances:P1 o 10 4; 2Dw2-test on point distributions:P2 o 10 4; Supplementary Fig. 2a,band Supplementary Note 7 online), confirming publishedresults11,12. Notably, the territory clearly split into two regions:one close to the nuclear center, as in the repressed state, anotherone close to the SPB (Fig. 3b). Combined with the earlier observa-tion thatGAL1 mRNA is detected when the locus is preferentiallyperipheral11, this result supports a model where the on/offstates oftranscription correspond to twolocation states. Note that thebimodality disappeared in the absence of nucleolar alignment(Fig. 3c,d) and was therefore not apparent from previous staticanalyses. This result lends strongstatistical support to earlierdynamic data suggesting two spatial states forGAL1 (ref. 11).

An alternative possibility is that the switch in growth mediumaltered the cell cycle, which in turnmight affect locus positioning25.However the proportion of cells exhibiting peripheral versus centralGAL1 was similar in G1 and S phase (data not shown). Thenucleolar volume in the presence of galactose was roughly halvedcompared to that in glucose, while nuclear volumes were reducedonly slightly (Table 1). To examine whether relocalization resultedfrom medium-dependent alterations of nucleolar morphology, wemappedURA3 , whose expression is not affected by the switch fromglucose to galactose, and which occupied a territory similar toGAL1 in glucose (Figs. 1f and 3a). No significant change inURA3localization was visible in galactose (P1 ¼ 0.12; P2 ¼ 0.26),confirming the activation-dependent nature ofGAL1 territoryremodeling (Supplementary Fig. 4a,b online).We next examined GAL2, which is activated by the same

upstream activated sequences and binding factors asGAL110.Like GAL1, GAL2 is known to relocalize toward the peripheryupon activation10, suggesting that both genes are recruited tonuclear pores where they possibly share the same transcriptionmachinery3,26. Probability maps showed thatGAL2 was confinedto a small (0.86 mm3) territory between the nucleolus and thenuclear center when repressed (Fig. 3e). Upon galactose induction,the GAL2 territory slightly shifted toward the nuclear periphery(P1 o 10 4), consistent with earlier findings10 (Fig. 3f,m).However, whereas activatedGAL1 partly concentrated near thenuclear periphery and the SPB, activatedGAL2 accumulatednear the nucleolus. Thus,GAL2 was juxtaposed less frequentlywith the nuclear envelope thanGAL1 but more often withthe nucleolus. Furthermore, activatedGAL1 and GAL2 occupiedlargely distinct territories and are thus unlikely to be transcribed bythe same transcription machinery (Fig. 3b,f ).

Pmax = 2.1n = 1,913

a SPB

0

Pmax

Pmax = 1.14 Pmax = 0.93 Pmax = 0.44n = 1,395n = 657n = 2,663 Probability density (μm

–3)n = 2,000 Pmax = 0.3

n = 100

b c d e

n = 100 n = 100 n = 100 n = 100Pmax = 2.08 Pmax = 1.91

n = 1,395n = 657n = 2,663n = 1,913 n = 2,000

Pmax = 2.32 Pmax = 0.73 Pmax = 1.52

Pmax = 0.53 Pmax = 0.38 Pmax = 0.47 Pmax = 0.44 Pmax = 0.31

rDNA CEN Tel VIIL Random

g h i jf

l m n ok

Subsampled Subsampled Subsampled Subsampled Subsampled

Not aligned Not aligned Not aligned Not aligned Not aligned

Figure 2 | Validation of mapping method for different loci and the SPB. (a–o) Probability maps as inFigure 1f (a–d, simulated map ine), maps obtained usingonly 100 cells (f–j) and maps obtained without alignment of the nucleolar centroid (k–o), of the SPB protein Spc29 (a,f ,k), rDNA locus (b,g, l), centromericplasmid (c,h,m), subtelomere on the left arm of chromosome 7 (d,i ,n) and a simulated point randomly located within the nuclear volume (e, j,o). The color barindicates probability density from 0 toPmax. Scale bar, 1mm.

1034 | VOL.5 NO.12| DECEMBER 2008| NATURE METHODS

ARTICLES

Gene TerritoriesData taken fromA. B. Berger, G. G. Cabal, E. Fabre, T. Duong, H. Buc, U. Nehrbass, et al. High-resolution statistical mapping reveals gene territories in live yeast. Nat Methods, 5(12):1031–7, 2008

Transcriptional Regulatory Network Shapes the Genome Structure of Saccharomyces cerevisiae Songling Li and Dieter W. Heermann, Nucleus. 2013 May-Jun;4(3):216-28.

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Heermann, Heidelberg University, 2015

Yeast

10-8

10-6

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100

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uenc

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slope = -1.55

ExperimentFitted Line

Data: Justin O‘Sullivan

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slope = -1.55

Gene Prox ModelFitted Line

Transcriptional Regulatory Network Shapes the Genome Structure of Saccharomyces cerevisiae Songling Li and Dieter W. Heermann, Nucleus. 2013 May-Jun;4(3):216-28.

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Heermann, Heidelberg University, 2015

Human Chromosomes

Diffusion-Driven Looping Provides a Consistent Framework for Chromatin Organization Manfred Bohn and Dieter W. HeermannPLoS ONE 5(8): e12218. doi:10.1371/journal.pone.0012218 (2010)

Ansatz: Dynamic Loop Model + gene expression.

Human Chromosomes

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Heermann, Heidelberg University, 2015

Chromosome 11

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. disp

lace

men

t R

2 [

µm2]

mea

n sq

. disp

lace

men

t R

2 [

µm2]

Human Chromosomes

R

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Heermann, Heidelberg University, 2015

2d

d1

Diffusion-Driven Looping Provides a Consistent Framework for Chromatin Organization Manfred Bohn and Dieter W. HeermannPLoS ONE 5(8): e12218. doi:10.1371/journal.pone.0012218 (2010)

Human Chromosomes

Page 46: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

Chromosome 11

genomic distance [Mb]

6

4

2

0 10 3020 50 60 7040

Chromosome 1

0

2

4

0 10 3020genomic distance [Mb]

0

8

6 10

60 70 80genomic position [Mb]

Chromosome 11

med

ian tr

ansc

riptio

n

90 100 110 120 1300

100

200

050 60 70 80

genomic position [Mb]

Chromosome 1

Chromosome 11

med

ian tr

ansc

riptio

n

100

200

0

1

2

3

0 1 2 3

genomic distance [Mb]

mea

n sq

. disp

lace

men

t R

2 [

µm2]

0

4

6

0 2 4 6 8 10 12

genomic distance [Mb]

A

B

C

2

4 8

Chromosome 1

mea

n sq

. disp

lace

men

t R

2 [

µm2]

mea

n sq

. disp

lace

men

t R

2 [

µm2]

mea

n sq

. disp

lace

men

t R

2 [

µm2]

The dynamic loop model very well explains differences between ridges and anti-ridges by different local looping probabilities.

0

2

4

6

8

10

0 2 4 6 8 10 12

mean

square

displacem

ent

⌦ R2↵

genomic distance [Mb]

chr 11 ridge

chr 11 anti-ridge

model in ridge region

model in anti-ridge region

Human Chromosomes

Page 47: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

Chromosome 11

genomic distance [Mb]

6

4

2

0 10 3020 50 60 7040

Chromosome 1

0

2

4

0 10 3020genomic distance [Mb]

0

8

6 10

60 70 80genomic position [Mb]

Chromosome 11

med

ian tr

ansc

riptio

n

90 100 110 120 1300

100

200

050 60 70 80

genomic position [Mb]

Chromosome 1

Chromosome 11

med

ian tr

ansc

riptio

n

100

200

0

1

2

3

0 1 2 3

genomic distance [Mb]

mea

n sq

. disp

lace

men

t R

2 [

µm2]

0

4

6

0 2 4 6 8 10 12

genomic distance [Mb]

A

B

C

2

4 8

Chromosome 1

mea

n sq

. disp

lace

men

t R

2 [

µm2]

mea

n sq

. disp

lace

men

t R

2 [

µm2]

mea

n sq

. disp

lace

men

t R

2 [

µm2]

The dynamic loop model also reproduces the experimental findings on the scale of a complete chromsome arm.

0

2

4

6

8

10

12

0 10 20 30 40 50 60 70 80

mean

square

displacem

ent

⌦ R2↵

genomic distance [Mb]

chr 11 long distance

RL model for long distance measurements

Human Chromosomes

Page 48: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

1e-07

1e-06

1e-05

0.0001

0.001

0.01

0.1

1

10 100

relative

abundanceh(l)

size of contact l

⇠ l�2.4

⇠ l�2

⇠ l�0.81

0 50 100 150 200 250

average loop number per conformation

2d

d1

Human Chromosomes

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Heermann, Heidelberg University, 2015

Agrees with Sandra Goetze et. al. MOLECULAR AND CELLULAR BIOLOGY, June 2007, p. 4475–4487

Human Chromosomes

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Heermann, Heidelberg University, 2015

We understand the folding pattern of chromosomes in interphase:

Folding is governed by loops on all scales mediated by proteins (transcptional hubs, ...)

Human Chromosomes

Page 51: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

T.Cremer and C. Cremer, Nature Reviews Genetics vol. 2, no. 4, pp. 292-301 (April, 2001)

Why do chromosomes not mix?

Human Chromosomes

Page 52: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

r

REPLUSIVE FORCE

radius of gyration

overlap between

chromosomes

Human Chromosomes

Page 53: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

A. Linear chains B. 45 loops per chain C. 92 loops per chain

0512

1024

bead number

0 512 1024

0512

1024

bead number

0 512 1024

0512

1024

bead number

0 512 1024

Human Chromosomes

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Heermann, Heidelberg University, 2015

Human Chromosomes

Ansatz: Dynamic Loop Model + gene expression.

Chromosomes in Metaphase

Zhang Y, Heermann DW (2011) Loops Determine the Mechanical Properties of Mitotic Chromosomes. PLoS ONE 6(12): e29225. doi:10.1371/journal.pone.0029225

60 70 80genomic position [Mb]

Chromosome 11

media

n tra

nscr

iptio

n

90 100 110 120 1300

100

200

60 70 80

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Heermann, Heidelberg University, 2015

Chromosomes in Metaphase

Zhang Y, Heermann DW (2011) Loops Determine the Mechanical Properties of Mitotic Chromosomes. PLoS ONE 6(12): e29225. doi:10.1371/journal.pone.0029225

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Heermann, Heidelberg University, 2015

Chromosomes in Metaphase

Reversible and Irreversible Unfolding of Mitotic Newt Chromosomes by Applied ForceMichael Poirier, Sertac Eroglu Didier Chatenay, and John F. Marko Mol Biol Cell. 2000 January; 11(1): 269–276.

Page 57: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

Chromosomes in Metaphase

Structural changes of Xenopus sperm nuclei in mitotic egg extract; control sperm nuclei (a), decondensed sperm after 10 min of incubation in the extract (b), chromosomal structures (c–g) found after 30, 60, 90, 120, and 150 min, respectively.

Houchmandzadeh B , Dimitrov S J Cell Biol 1999;145:215-223

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Heermann, Heidelberg University, 2015

Chromosomes in Metaphase

Page 59: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

Summary

Human Chromosomes

• FISH experiments on single chromosomes

• Bio-chemical experiments (4c, Hi-C)

• Partial genome staining experiments

• Whole genome staining experiments

• Mechanical data (metaphase)

Escherichia coli Yeast

Dynamic Loop Model + Biological Input:

Page 60: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

The Physical Architecture of the Genome: Common Principles in

Prokaryotes and Eukaryotes

The principles are loops, entropy and confinment

Unified Model

Page 61: The Physics of Chromosomes: Loops and Entropy, that's what it's … · 2017-03-26 · stfq_tfaq fole nohq icd yjev aer gyrb glyu cira ompa exu mpl rbs glk cspd topa hcha pot gar heml

Heermann, Heidelberg University, 2015

Manfred BohnPhilipp Diesinger

Roel van DrielSandra GötzeMariliis Tark

Hans-Jörg JerabekSongling Li

Miriam FritscheChristoph CremerLindsay Shopland

Paul WigginsJörg Bewersdorf

Heidelberg Graduate School of

Mathematical and Computational

Methods for the Sciences

Spatio/Temporal Probabilistic Graphical

Models and Applications in Image Analysis

Center for Interdisciplinary Scientific Computing,

Heidelberg

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Heermann, Heidelberg University, 2015

Thank you for your attention!