Toward a unified physical model of nucleosome patterns flanking transcription start sites

Möbius, Wolfram; Osberg, Brendan; Tsankov, Alexander M.; Rando, Oliver J.; Gerland, Ulrich

doi:10.1073/pnas.1214048110

Cited by 42 publications

(74 citation statements)

References 33 publications

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“…Our model attributes short interdyad distances seen in the experiment to intrinsic energetics of histone-DNA interactions. It significantly extends previous work (18)(19)(20)(21) by considering sequence-dependent formation of partially wrapped nucleosome arrays and by proposing a histone-DNA binding energy profile based on nucleosome crystal structures. Using our approach, we reproduce nucleosome occupancies and average lengths of wrapped DNA in the vicinity of transcription start sites (TSSs).…”

supporting

confidence: 63%

Ubiquitous nucleosome crowding in the yeast genome

Chereji¹,

Morozov

2014

Proc. Natl. Acad. Sci. U.S.A.

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Nucleosomes may undergo a conformational change in which a stretch of DNA peels off the histone octamer surface as a result of thermal fluctuations or interactions with chromatin remodelers. Thus, neighboring nucleosomes may invade each other's territories by DNA unwrapping and translocation, or through initial assembly in partially wrapped states. A recent high-resolution map of distances between dyads of neighboring nucleosomes in Saccharomyces cerevisiae reveals that nucleosomes frequently overlap DNA territories of their neighbors. This conclusion is supported by lower-resolution maps of S. cerevisiae nucleosome lengths based on micrococcal nuclease digestion and paired-end sequencing. The average length of wrapped DNA follows a stereotypical pattern in genes and promoters, correlated with the well-known distribution of nucleosome occupancy: nucleosomal DNA tends to be shorter in promoters and longer in coding regions. To explain these observations, we have developed a biophysical model that uses a 10-11-bp periodic histone-DNA binding energy profile. The profile is based on the pattern of histone-DNA contacts in nucleosome crystal structures, as well as the idea of linker length discretization caused by higher-order chromatin structure. Our model is in agreement with the observed genome-wide distributions of interdyad distances, wrapped DNA lengths, and nucleosome occupancies. Furthermore, our approach explains in vitro measurements of the accessibility of nucleosome-covered target sites and nucleosome-induced cooperativity between DNA-binding factors. We rule out several alternative scenarios of histone-DNA interactions as inconsistent with the genomic data.partially unwrapped nucleosomes | DNA accessibility | gene regulation E ukaryotic genomes are organized into arrays of nucleosomes (1). Each nucleosome consists of a stretch of genomic DNA wrapped around a histone octamer core (2). The resulting complex of DNA with histones and other regulatory and structural proteins is called chromatin (1). Arrays of nucleosomes form 10-nm fibers that resemble beads on a string and, in turn, fold into higher-order structures (3). Depending on the organism and cell type, 75-90% of genomic DNA is packaged into nucleosomes (1). Because nucleosomal DNA is wrapped tightly around the histone octamer, its accessibility to various DNA-binding proteins, such as repair enzymes, transcription factors (TFs), polymerases, and recombinases, is suppressed. The question of how cellular functions are carried out on the chromatin template is one of the outstanding puzzles in eukaryotic biology.Recently, nucleosome dyad positions and distances between dyads of neighboring nucleosomes were mapped genome-wide with high precision in Saccharomyces cerevisiae (4). The in vivo map was obtained by chemical modification of engineered histones, DNA backbone cleavage by hydroxyl radicals, and highthroughput sequencing (Fig. 1A). Although more precise than methods based on micrococcal nuclease (MNase) digestion, whose accuracy is affected by MNase...

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supporting

confidence: 63%

Ubiquitous nucleosome crowding in the yeast genome

Chereji¹,

Morozov

2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Using a computational approach, Mobius et al (76) recently modeled that mere inclusion of a dinucleosome clamp in the classical statistical positioning mechanism (29,30) can account for regular and constant spacing at barriers with fixed ϩ1 nucleosome even at low nucleosome density. This demonstrates that there is no need for a packing mechanism providing directionality against the barrier to explain how arrays with constant spacing are maintained at barriers despite lowered nucleosome density, which was observed in vitro and in vivo (16,(31)(32)(33)(34)(35).…”

Section: Discussionmentioning

confidence: 99%

Nucleosome Spacing Generated by ISWI and CHD1 Remodelers Is Constant Regardless of Nucleosome Density

Lieleg¹,

Ketterer

Nuebler

et al. 2015

Molecular and Cellular Biology

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Arrays of regularly spaced nucleosomes are a hallmark of chromatin, but it remains unclear how they are generated. Recent genome-wide studies, in vitro and in vivo, showed constant nucleosome spacing even if the histone concentration was experimentally reduced. This counters the long-held assumption that nucleosome density determines spacing and calls for factors keeping spacing constant regardless of nucleosome density. We call this a clamping activity. Here, we show in a purified system that ISWI-and CHD1-type nucleosome remodelers have a clamping activity such that they not only generate regularly spaced nucleosome arrays but also generate constant spacing regardless of nucleosome density. This points to a functionally attractive nucleosome interaction that could be mediated either directly by nucleosome-nucleosome contacts or indirectly through the remodelers. Mutant Drosophila melanogaster ISWI without the HAND-SANT-SLIDE (HSS) domain had no detectable spacing activity even though it is known to remodel and slide nucleosomes. This suggests that the role of ISWI remodelers in generating constant spacing is not just to mediate nucleosome sliding; they actively contribute to the attractive interaction. Additional factors are necessary to set physiological spacing in absolute terms.

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“…However, [15] mainly focuses on how dinucleotide periodicity affects nucleosome positions in synthetic DNA sequences and genome-wide nucleosome occupancy, and it does not analyze other sequence features such as GC and polyA ; it also does not address genome-wide nucleosome positioning; finally, the proposed energy model uses artificial sinusoidal functions. Both [25] and [26] mostly focus on the effect of nucleosome unwrapping. In particular, [25] does not study the sequence-dependence of nucleosome occupancy and positioning.…”

Section: Methodsmentioning

confidence: 99%

“…3.2). Our CEM is inspired by similar optimization-based approaches [15, 25, 26], but contains no artificial components (as in [15, 26]) and provides a flexible framework that can incorporate various regulatory factors, such as chromatin remodelers, which may affect nucleosome occupancy and positioning (Sec. 5).…”

Section: Introductionmentioning

confidence: 99%

A unified computational framework for modeling genome-wide nucleosome landscape

Finnegan

Song

2018

Phys. Biol.

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Nucleosomes form the fundamental building blocks of eukaryotic chromatin, and previous attempts to understand the principles governing their genome-wide distribution have spurred much interest and debate in biology. In particular, the precise role of DNA sequence in shaping local chromatin structure has been controversial. This paper rigorously quantifies the contribution of hitherto-debated sequence features – including G+C content, 10.5-bp periodicity, and poly(dA:dT) tracts – to three distinct aspects of genome-wide nucleosome landscape: occupancy, translational positioning and rotational positioning. Our computational framework simultaneously learns nucleosome number and nucleosome-positioning energy from genome-wide nucleosome maps. In contrast to other previous studies, our model can predict both in-vitro and in-vivo nucleosome maps in S. cerevisiae. We find that although G+C content is the primary determinant of MNase-derived nucleosome occupancy, MNase digestion biases may substantially influence this GC dependence. By contrast, poly(dA:dT) tracts are seen to deter nucleosome formation, regardless of the experimental method used. We further show that the 10.5-bp nucleotide periodicity facilitates rotational but not translational positioning. Applying our method to in-vivo nucleosome maps demonstrates that, for a subset of genes, the regularly-spaced nucleosome arrays observed around transcription start sites can be partially recapitulated by DNA sequence alone. Finally, in-vivo nucleosome occupancy derived from MNase-seq experiments around transcription termination sites can be mostly explained by the genomic sequence. Implications of these results and potential extensions of the proposed computational framework are discussed.

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Toward a unified physical model of nucleosome patterns flanking transcription start sites

Cited by 42 publications

References 33 publications

Ubiquitous nucleosome crowding in the yeast genome

Ubiquitous nucleosome crowding in the yeast genome

Nucleosome Spacing Generated by ISWI and CHD1 Remodelers Is Constant Regardless of Nucleosome Density

A unified computational framework for modeling genome-wide nucleosome landscape

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