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3DAROC18 Summary Day #1 3DAROC18 Summary day #1 David Castillo, François Serra & Marc A. Marti-Renom Structural Genomics Group (CNAG-CRG) Data groups Experimental observations Statistical rules Laws of physics Integrative modeling Data collection Data interpretation Representation Modeling Sampling Model analysis LETTERS NATURE XVI ARTICLES 0 I 0 II 0 Chromosome a 0 c XV III 0 I II III IV V VI VII VIII IX X XI XII XVI XIII 1 XIV I XV II Downloaded from genome.cshlp.org0 on May 30, 2012 - Published by Cold Spring Harbor Laboratory Press IV III 0.5 XIV IV V 0 0 0 VI VII Molecular Cell XIII V VIII –0.5 0 IX 0 0VI 1.0 Figure 6 Population-based analysis of 3.0 Chromosome X −1 Chr18 XI a bVII XII XII –1.5 The 3D Architecture of a Bacterial Genome 0 XIII chromosome territory localizations in the nucleus. 0 VIII XIV 0 X 2 XI IX Chr19 0 0 −2 X XV 6 XVI 18 10 Principles3 of 3D genome organization in yeast 780 5 2.5 770 760 750 7 740 730 0 (a) The distribution of the radial positions for 10 20 30 8 720 40 710 50 60 12 70 13 700 80 0.8 690 90 I 680 100 1 15 9 4 b 670 110 d 120 660 130 650 140 0 chromosomes 18 (red dashed line) and 19 (blue 640 15 630 160 11 620 170 8 3D modeling of genomic180 domains: other methods 610 190 60 14 2.0 0 200 590 210 580 220 6 1 solid line), calculated from the genome structure 570 230 20 560 550 0 540 10 20 4 530 30 0.6 Centromeres16 520 40 21 19 17 population. Radial positions are calculated for 510 50 Telomeres 500 60 Early origins 490 70 2 1.5 80 80 22 Late origins 4 470 90 Breakpoints (Scer) 100 Percentage of positive interactions 460 110 Breakpoints (Scer and Kwal) 4500 12 44 1 0 0 the center of mass of each chromosome and are 14030 430 00.20.40.60.81 Density 150 A 420 16 410 170 Percentage of negative interactions 400 180 0 190 390 200 380 210 220 230 370 240 250 XIV 360 270 260 350 340 330 320 310 300 290 given as a fraction of the nuclear radius. (b) The 1.0 (i) 280 0.4 (ii) (iii) (iv) Figure 4 | Inter-chromosomal interactions. a 0.0 , Circos diagram showing chromosome I, and a distinct region of corresponding size on chromosome average radial position of all chromosomes plotted interactions between chromosome I and the remaining chromosomes. All 16 XIV. c, Inter-chromosomal interactions between all pairs of the 32 yeast a yeast chromosomesVisualizing are aligned circumferentially, and arcs depict distinct Relative radial position chromosomal arms (the 10 kb region starting from the midpoint 3D of the Genomes inter-chromosomal interactions. Bold red hatch marks correspond to centromere in each arm is excluded). For each chromosome, the shorter arm against their size. Error bars, s.d. (c) Clustering of 0.5 centromeres. To aid visualization of centromere0.5 clustering, these is always placed before the longer arm. Note that the arms of small representations were created using the overlap set of inter-chromosomal 0.2chromosomes tend to interact with one another. The colour scale chromosomes with respect to the average distance interactions identified from both HindIII and EcoRI libraries at an FDR corresponds to the natural log of the ratio of the observed versus expected threshold of 1%. Additional heat maps1.1 and Circos diagrams are provided in number of interactions (see Supplementary Materials). d, Enrichment of Supplementary Fig. 9. b, Circos diagram, generated using the inter- interactions between centromeres, telomeres, early origins of replication, 0 chromosomal interactions identified from the HindIII libraries at an FDR and chromosomal breakpoints. To measure enrichment of strong Spatial Organizations of Chromosomes between the center of mass of each chromosome threshold of 1%, depicting the distinct interactions between a small and a interactions with respect to a given class of genomic loci, we use receiver large chromosome (I and XIV, respectively).1.7 Most of the interactions operating curve (ROC) analysis. pair in the genome structure population. The 0 0.2 0.4 between0.6 these two chromosomes0.8 primarily involve1.0 the entirety of 50 100 150 200 250 chromosomal pairings, except for pairing between the two smallest depict intra-chromosomal folding, we incorporated a metric that Relativearms distance (1R and 9R) (Supplementary2.1 Fig. 16a). However, the preference converts interaction probabilitiesChromosome into nuclear distances (assigningsize (Mb) clustering dendrogram, which identifies two for intra-chromosomal arm pairing versus inter-chromosomal arm 130 bp of packed chromatin a length of 1 nm, ref. 30) (Supplemen- b from nuclearpairing center decreased with increasing distance from centromeres tary Figs 17 and 18 and Supplementary Methods). Using this ruler, dominant clusters is shown on top. The matrix ofJhunjhunwala (2008) Cell (Supplementary Fig. 16 b–d). These2.5 observations indicate that yeast we calculated the spatial distances between all possible pairings of the Hu (2013) PLoS Computational Biology chromosome arms are highly flexible. 16 centromeres (Supplementary Tables 14 and 15) The results are average distances between pairs of chromosomes Combining our set of 4,097,539 total and 306,312 distinct inter- consistent with previous observations12. Kalhor (2011) Nature Biotechnology! Cluster 2 actions with known spatial distances3.0 that separate sub-nuclear land- The resulting map resembles a water lily, with 32 chromosome c 12 d marks , we derived a three-dimensional map of the yeast genome. To arms jutting out from a base of clustered centromeres (Fig. 5). Tjong (2012) Genome Research is shown at the bottom. The intensity of blue ClusterDuan 1 Minus Probe Genome Position (Mb) (2010) Nature 3.5 I I Figure 5 | Three-dimensionalCluster model 1 of the yeast II II genome. Two views representing two different color increases with decreasing distance. (d) (Left III III IV IV angles are provided. Chromosomes are coloured 4.0 V V VI VI as in Fig. 4a (also indicated in the upper right). All VII VII panels) The density contour plot of the combined VIII VIII chromosomes cluster via centromeres at one pole 0.0IX 0.5 1.1 1.6 2.1 2.5IX 3.1 3.6 4.0 X X of the nucleus (the area within the dashed oval), XI XI 15 10 Nucleic Acids Research, 2010 XII XII while chromosome XII extends outward towards localization probability for all the chromosomes in XIII Plus Probe Genome PositionXIII (Mb) XIV XIV the nucleolus, which is occupied by rDNA repeats 11 XV XV (indicated by the white arrow). After exiting the XVI XVI 1 nucleolus, the remainder of chromosome XII cluster 1 (top panel) and cluster 2 (bottom panel) A B B interacts with the long arm of chromosome IV. 14 10Kb Cluster 1 Cluster 2 Cluster 3 Cluster 4 A10a calculated from all the structures in the genome 20 A1 A2 A3 A4 A5 A6 A7 A9 A11 A13 16 3' 5' structure population. The rainbow color-coding A10b 21 6 19 3' 5' on the central nuclear plane ranges from blue 4 5 22 ©2010 Macmillan Publishers Limited. All rights reserved (minimum value) to red (maximum value).http://genomebiology.com/2009/10/4/R37 17 Genome Biology 2009, Volume 10, Issue 4, Article R37 Fraser et al. R37.12 2 4 (Right panels) A representative genome 6 3 X Cluster 2 2 structure from the genome structure population. 3 HoxA genes Base density (kb) Figure 5.2008 3D Topology of the(a) Immunoglobulin Heavy-Chain Locus(b) o o TECH NICAL REo P ORTS o 2014 10 A2A1 A3 A4 A5 A6 1 Downloaded from Nucleic Acids Research, 2012, Vol. 40, No. 16 7723 Chromosome territories are shownThe for 3D topologyall the of the Igh locus in pre-pro-B and pro-B cells was resolved using trilateration. The relative positions of 12 genomic markers180 spanning the entire 180 180 180 5 A7 A9 A10b A11 A13 immunoglobulin heavy-chain locus were computed. Two different views are shown for both cell types. 0 7 0 20 40 60 80 100 120 140 160 chromosomes in cluster 1 (top) and(A) 3D all Topology the of the Igh locus in pre-pro-B cells. D 8 Figure 4 3D models of the ENm008Genomic ENCODE Position (kb) region containing the chromosomes in clusters 2 (bottom).(B) 3D TopologyThe of the Igh locus in pro-B cells.18 Grey objects indicate CH regions and the 30 flanking region of the Igh locus. Blue objects indicate proximal VH a b regions. Green objects indicate distal VH regions. Red line indicates the linker connecting-globin the proximallocus. V(Haand) 3D JH structureregions. Linkers of the are indicatedGM12878 only to models show represented 12 http://nar.oxfordjournals.org All rights reserved. connectivity. C 10Kb localization probabilities are calculated following 13 by the centroid of cluster 1. The 3D model is A10acolored as in its linear . A1 A2 A3 A4 A5 A6 A7 A9 A11 A13 28 9 3' representation 5'(Fig. 1a). Regulatory elements are represented as spheres a previously described procedure from. the spatial distance measurements4 directly to the cumula- conclude that it is the Igh topology3' that mechanistically permits 5' colored red (HS40), orange (other HSs) and greenA10b (CTCF). (b) 3D tive frequency distributions as predicted by4 a13 3D random18 7 walk10 long-rangeX 2 22 genomic21 20 interactions1 15 to occur in pro-B cells with Inc (see Experimental Procedures for details).
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