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Spatially Confined Folding of Chromatin in the Interphase Nucleus

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Spatially Confined Folding of Chromatin in the Interphase Nucleus Spatially confined folding of chromatin in the interphase nucleus Julio Mateos-Langeraka,1,2, Manfred Bohnb,1, Wim de Leeuwc, Osdilly Giromusa, Erik M. M. Mandersa, Pernette J. Verschurea, Mireille H. G. Indemansd, Hinco J. Giermand, Dieter W. Heermannb, Roel van Driela, and Sandra Goetzea,3,4 aSwammerdam Institute for Life Sciences, University of Amsterdam, Kruislaan 318, 1098 SM Amsterdam, The Netherlands; bInstitute of Theoretical Physics, University of Heidelberg, Philosophenweg 19, 69120 Heidelberg, Germany; cNational Research Institute for Mathematics and Computer Science, Kruislaan 413, 1098 SJ Amsterdam, The Netherlands; and dDepartment of Human Genetics, Academic Medical Center, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands Edited by Jasper Rine, University of California, Berkeley, CA, and approved January 9, 2009 (received for review September 23, 2008) Genome function in higher eukaryotes involves major changes in Earlier studies have indicated that the structure of chromatin the spatial organization of the chromatin fiber. Nevertheless, our may be explained by a random walk (RW) model for distances understanding of chromatin folding is remarkably limited. Polymer up to 2 Mb, while on a larger scale there is a completely different models have been used to describe chromatin folding. However, behavior (4, 5). Folding at larger length scales has been explained none of the proposed models gives a satisfactory explanation of using several models. One approach has been to model the fiber experimental data. In particularly, they ignore that each chromo- as a random walk in a confined geometry (6). Two polymer some occupies a confined space, i.e., the chromosome territory. models have been proposed that introduce loops to explain Here, we present a polymer model that is able to describe key chromatin folding. One is the random-walk/giant-loop (RWGL) properties of chromatin over length scales ranging from 0.5 to 75 model, which assumes a RW-backbone to which loops of 3 Mb Mb. This random loop (RL) model assumes a self-avoiding random are attached (7). A second model, the multiloop-subcompart- walk folding of the polymer backbone and defines a probability P ment (MLS) model, proposes rosette-like structures consisting for 2 monomers to interact, creating loops of a broad size range. of multiple 120-kb loops (5, 8). None of these models is able to Model predictions are compared with systematic measurements of describe the folding of chromatin at all relevant length scales. All CELL BIOLOGY chromatin folding of the q-arms of chromosomes 1 and 11. The RL predict that the physical distance between 2 FISH markers model can explain our observed data and suggests that on the monotonously increases with the genomic distance. Clearly, this tens-of-megabases length scale P is small, i.e., 10–30 loops per 100 is incorrect at bigger length scales, since the chromatin fiber is Mb. This is sufficient to enforce folding inside the confined space geometrically confined by the dimensions of the cell nucleus. of a chromosome territory. On the 0.5- to 3-Mb length scale More so, individual chromosomes have been shown to occupy chromatin compaction differs in different subchromosomal do- subnuclear domains that are much smaller than the nucleus mains. This aspect of chromatin structure is incorporated in the RL itself, i.e., the chromosome territories with sizes in the range of model by introducing heterogeneity along the fiber contour length 1 to a few micrometers (9). Evidently, an intrinsic property of the due to different local looping probabilities. The RL model creates chromatin fiber inside the cell nucleus is that it assumes a a quantitative and predictive framework for the identification of compact state that cannot be described by classic polymer nuclear components that are responsible for chromatin–chromatin models. This raises the fundamental question what physical interactions and determine the 3-dimensional organization of the principles make chromatin to fold in a limited volume. chromatin fiber. How can be explained that a polymer folds such that, irre- spective of the length of the polymer, its physical extend does not genome organization ͉ polymer model ͉ chromatin folding increase? We have shown that this can be achieved by bringing parts of the polymer together that are nonadjacent along the he chromatin fiber inside the interphase nucleus of higher contour of the polymer, thus forming loops on all length scales Teukaryotes is folded and compacted on several length scales. (10). There is extensive experimental evidence that chromatin On the smallest scale the basic filament is formed by wrapping loops exist in the interphase nucleus. Various studies have double-stranded DNA around a histone protein octamer, form- indicated that the chromatin fiber forms loops that at their bases ing a nucleosomal unit every Ϸ200 bp. This beads-on-a-string may be attached to a still poorly defined structure that is called type filament in turn condenses to a fiber of 30-nm diameter, nuclear scaffold/matrix (11). Recent investigations indicate that which detailed organization is still under debate (1–3). At bigger the formation of chromatin loops involves specific proteins, length scales the spatial organization of chromatin in the inter- including SatB1 (12), CTCF and other insulator binding proteins phase nucleus is even more unclear. Imaging techniques do not allow one to directly follow the folding path of the chromatin fiber in the interphase nucleus. Therefore, indirect approaches Author contributions: J.M.-L., E.M.M.M., P.J.V., R.v.D., and S.G. designed research; J.M.-L., O.G., and S.G. performed research; W.d.L., M.H.G.I., and H.J.G. contributed new reagents/ have been used to obtain information about chromatin folding. analytic tools; J.M.-L., M.B., D.W.H., and S.G. analyzed data; and J.M.-L., M.B., D.W.H., One way, pursued in this study, is fluorescence in situ hybrid- R.v.D., and S.G. wrote the paper. ization (FISH) to measure the relationship between the physical The authors declare no conflict of interest. ␮ distance between genomic sequence elements (in m) and their This article is a PNAS Direct Submission. genomic distance (in megabases). There have been several 1J.M.-L. and M.B. contributed equally to this work. attempts to explain the folding of chromatin in the interphase 2Present address: Institute of Human Genetics, Centre National de la Recherche Scienti- nucleus using polymer models. The strength of polymer models fique, Rue de la Cardonille 141, 34396 Montpellier, France. is their ability to make predictions on the structure of chromatin 3Present address: Center for Model Organism Proteomes, Institute of Molecular Biology, by pointing out the driving forces for observed folding motifs. University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland. These predictions can then be tested experimentally. However, 4To whom correspondence should be addressed. E-mail: [email protected]. a polymer model that is able to explain chromatin folding This article contains supporting information online at www.pnas.org/cgi/content/full/ spanning different length scales is still lacking. 0809501106/DCSupplemental. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0809501106 PNAS Early Edition ͉ 1of6 Downloaded by guest on September 26, 2021 Fig. 1. The random loop polymer model. (A) The diagram schematically shows a small part of the polymer, which is build up of loops with a broad range of sizes. The attachment points are marked by colored circles. (B) Molecular dynamics simulations of a polymer with randomly positioned loops. The relationship between the mean square displacement between 2 monomers and their contour distance is shown for different values of P. P denotes the probability that a pair of monomers interacts. Looping probabilities range from 13 (P ϭ 3 ϫ 10Ϫ4) to 133 (P ϭ 3 ϫ 10Ϫ3) loops per chain. The chain length is N ϭ 300 monomers. The increase in mean square displacement at Nm Ͼ 250 is due an increased freedom of the chain ends. (C) Comparison of simulations of the RL model with experimental data. The polymer chain length is N ϭ 300 monomers and a coarse-grained monomer is equivalent to 500 kb. At this scaling the RL model correctly predicts the leveling off at genomic distances above Ϸ10 Mb. Simulations are shown for 4 P values (range 5 ϫ 10Ϫ4 to 3 ϫ 10Ϫ3), corresponding to 1–9 loops per 10 Mb. The experimental data from Fig. 2 are shown. (13). Other studies show long-range chromatin-chromatin inter- are not adjacent along the backbone interact with a probability actions due to transcription factories in which transcriptionally P. As a consequence loops on all length scales are generated active genes at different positions on a chromosome and from randomly as illustrated in Fig. 1A. Obviously, assuming random different chromosomes, come together (14). loop formation as we do in the RL model is an approximation, The random loop (RL) polymer model offers a unified since in the living cell chromatin-chromatin fiber interactions description of chromatin folding at different length scales (10). will most likely depend on physical interactions between specific We show that the RL model adequately describes a large set of regulatory elements. experimental data that systematically measure the in situ 3D The RL model introduces 2 important features that have not distances between pairs of FISH probes that mark specific points been addressed by polymer models for chromatin up to now. on the chromatin fiber of the q arms of chromosomes 1 and 11 First, it takes into account that intrapolymer interactions, i.e., in human primary fibroblast. We show that the RL model loop-attachment points, vary from cell to cell and therefore presents a simple explanation of the spatial confinement of the measurements are an average over the ensemble that is repre- chromatin fiber in chromosome territories.
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