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DNA Physical Properties Determine Nucleosome Occupancy from Yeast to Fly. Vincent Miele, Cédric Vaillant, Yves D’Aubenton-Carafa, Claude Thermes, Thierry Grange

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DNA Physical Properties Determine Nucleosome Occupancy from Yeast to Fly. Vincent Miele, Cédric Vaillant, Yves D’Aubenton-Carafa, Claude Thermes, Thierry Grange DNA physical properties determine nucleosome occupancy from yeast to fly. Vincent Miele, Cédric Vaillant, Yves d’Aubenton-Carafa, Claude Thermes, Thierry Grange To cite this version: Vincent Miele, Cédric Vaillant, Yves d’Aubenton-Carafa, Claude Thermes, Thierry Grange. DNA physical properties determine nucleosome occupancy from yeast to fly.. Nucleic Acids Research, Oxford University Press, 2008, 36 (11), pp.3746-56. 10.1093/nar/gkn262. hal-00319296 HAL Id: hal-00319296 https://hal.archives-ouvertes.fr/hal-00319296 Submitted on 30 May 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution - NonCommercial| 4.0 International License 3746–3756 Nucleic Acids Research, 2008, Vol. 36, No. 11 Published online 17 May 2008 doi:10.1093/nar/gkn262 DNA physical properties determine nucleosome occupancy from yeast to fly Vincent Miele1,Ce´ dric Vaillant1,2, Yves d’Aubenton-Carafa3, Claude Thermes3 and Thierry Grange4,* 1Laboratoire Statistique et Ge´ nome, CNRS/INRA/UEVE, 523 place des Terrasses, 91000 Evry, 2Laboratoire Joliot-Curie and Laboratoire de Physique, ENS-Lyon, 46 alle´ e d’Italie, 69364 Lyon Cedex 07, 3Centre de Ge´ ne´ tique Mole´ culaire, CNRS, Alle´ e de la Terrasse, 91198 Gif-sur-Yvette and 4Institut Jacques Monod, CNRS, Universite´ s Paris 6-7, 2 Place Jussieu, 75251 Paris Cedex 05, France Received January 7, 2008; Revised April 17, 2008; Accepted April 21, 2008 ABSTRACT is composed of about 147 DNA base pairs wrapped around a histone octamer (1,2). Nucleosomes, as well as Nucleosome positioning plays an essential role in the enzymes that remodel and modify them, are key cellular processes by modulating accessibility of regulators of genome activity (3). Nucleosome positioning DNA to proteins. Here, using only sequence-depen- can affect the accessibility of underlying DNA to the dent DNA flexibility and intrinsic curvature, we pre- nuclear environment and as such plays an essential role in dict the nucleosome occupancy along the genomes the regulation of cellular processes (4,5). Nucleosome of Saccharomyces cerevisiae and Drosophila mela- formation and/or positioning depends on intrinsic proper- nogaster and demonstrate the predictive power and ties of the DNA sequence such as flexibility or natural universality of our model through its correlation with bending of adjacent base pairs (6–10). In particular, experimentally determined nucleosome occupancy repetitive occurrences of curved DNA motifs positioned at data. In yeast promoter regions, the computed intervals of one turn of the double helix can contribute to average nucleosome occupancy closely superim- DNA curvature and facilitate its wrapping around the histone surface. In yeast, the contribution of the DNA poses with experimental data, exhibiting a _200 bp sequence to nucleosomal organization has been observed region unfavourable for nucleosome formation bor- at a few promoters (11,12). Nucleosomal organization is dered by regions that facilitate nucleosome forma- generally analysed by using micrococcal nuclease (MNase) tion. In the fly, our model faithfully predicts promoter digestion of chromatin. In chromatin, MNase cleaves strength as encoded in distinct chromatin archi- DNA preferentially within the linker region and at tectures characteristic of strongly and weakly nuclease-hypersensitive sites found at regulatory regions expressed genes. We also predict that nucleosomes such as promoters. To perform large-scale studies of are repositioned by active mechanisms at the nucleosomal organization, the distribution of MNase majority of fly promoters. Our model uses only cleavage sites is determined throughout genomic regions basic physical properties to describe the wrapping or in the whole genome by means of either oligonucleotide of DNA around the histone core, yet it captures a tiling arrays or massive sequencing (12–15). Unfortu- substantial part of chromatin’s structural complex- nately, systematic biases such as MNase cleavage specifi- ity, thus leading to a much better prediction of nucle- city, composition-dependent labelling or hybridization biases inherent to the microarray procedure were generally osome occupancy than methods based merely on not assessed. Such studies have nevertheless provided data periodic curved DNA motifs. Our results indicate that sets that make it possible to analyse the parameters the physical properties of the DNA chain, and not just determining chromatin organization. In particular, the the regulatory factors and chromatin-modifying DNA sequence was proposed to play a role in yeast enzymes, play key roles in eukaryotic transcription. nucleosomal organization with particular emphasis on periodic occurrences of curved DNA motifs that were strongly preferred by nucleosomes (16,17). Correlation INTRODUCTION with the GC content of DNA was also observed (15,18). Eukaryotic chromosomes are packaged in condensed To what extent can nucleosome occupancy be deduced chromatin structures whose primary unit, the nucleosome, from the analysis of genome sequences? In the study *To whom correspondence should be addressed. Tel: +33 144 275707; Fax: +33 144 275716; Email: [email protected] The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint Authors ß 2008 The Author(s) This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Nucleic Acids Research, 2008, Vol. 36, No. 11 3747 presented here, we used only physical modelling of the where wrapping of DNA around nucleosomes to predict ab initio chromatin organization and its role in gene regulation j¼XiþLÀ1 without using any training or regression-based procedure. mði, LÞ¼ð1=LÞ mð j Þ: We also assessed some of the biases introduced by the j¼i experimental procedures. This allowed us to demonstrate The free-energy landscape is finally obtained by using the the predictive power of physical modelling in organisms as standard thermodynamical relation: diverse as yeast, fly and nematode. ÁFði Þ ÁEði Þ ¼ À ÁSði Þ: MATERIALS AND METHODS kBT kBT Physical model The energy profile can actually be decomposed into two We implemented ab initio prediction of nucleosome contributions: occupancy along DNA sequences by computing the free- ÁF ði, Þ¼ÁF ðiÞþÁF ði Þ, energy landscape associated with the bending of DNA tot i mean osc around histone octamers to form nucleosomes. To evaluate where: this elastic free-energy, we assumed that a DNA chain of Xiþ L length L is constrained at position i around the histone ÁFmean Að j Þ 2 2 2 ði Þ¼  ½ þ o1ð j Þþ o2ð j Þ octamer to form an ideal superhelix of radius R = 4.19 nm kBT 2 and pitch P = 2.52 nm (19). This geometry of the DNA j ¼ i 1 chain can be defined by the following roll, tilt and twist A3ð j Þ þ ð À Þ2 À ÁSði Þ angle distributions: 2 3 o3 1ð j Þ¼ sin ð! ð j À iÞþiÞ and: ! ð j Þ¼ cos ð! ð j À iÞþiÞ 2 iþXLÀ1 À1 ÁFosc 3ð j Þ¼2=10:3 bp ði Þ¼ Að j Þ½ o1ð j Þ sin !j À o2ð j Þ cos !j kBT j ¼ i for j ¼ i,...,i þ L À 1 and with: ¼ð2Þ2R=ðP2þð2RÞ2Þ, 2 2  cos ð!i þ Þ ! ¼ 3ð j Þ2P=ðP þð2RÞ Þ Assuming that the DNA i ! chain is an inextensible and unshearable elastic rod, the iþXLÀ1 elastic energy required to form such a superhelix depends þ Að j Þ½ o1ð j Þ cos !j þ o2ð j Þ sin !j solely on the roll, tilt and twist deformations given by: j¼i iþXLÀ1  sin ð!i þ iÞ ÁEði, LÞ A1 2 A2 2 ¼ ð 1 À o1Þ þ ð 2 À o2Þ kBT 2 2 2 j ¼ i A3 2 þ ð 3 À o3Þ , 2 (i) ÁFmeanðiÞ is the sum of the energies required (a) to form a straight fragment from the original intrinsi- where A , A and A are the stiffnesses associated with the 1 2 3 cally curved fragment and (b) to form the appro- tilt, roll and twist fluctuations around their equilibrium priately curved nucleosomal DNA. It depends mainly values o1, o2 and o3, respectively. These elastic para- meters depend on the sequence at positions j ¼ i, :::, iþ on the modulus of the intrinsic curvatures j o1, 2j of the DNA fragment. ÁFmeanðiÞ takes into account the L À 1 along the nucleosomal DNA. Equilibrium values o and stiffnesses are determined as in (10). We neglect contributions of DNA motifs that either increase or anisotropic bending deformations and we retain only the decrease the intrinsic curvature and as such predict the isotropic deformations controlled by the ‘isotropic’ stiff- regions with high nucleosome occupancy as well as à nucleosome instability regions. ness A ¼ðA1+A2Þ=2. We assume that Að j Þ¼A m ð j Þ, where Aà ¼ 50 nm is the stiffness of the ‘standard’ (ii) ÁFoscði, iÞ is the component that is dependent on the phase . It is a rapidly varying term in the case of (random) sequence and m, a sequence dependent mod- ulating factor. Similarly, for the twist stiffness we use: a uniformly fixed phase, i.e. it oscillates with a à 2=! 10:4 bp period. The amplitude of these A3ð j Þ¼A mð j Þ with A3 = 75 nm (20).
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