A unified computational framework for modeling genome-wide nucleosome landscape

Abstract

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.

Sensitive Automated Measurement of Histone-DNA Affinities in Nucleosomes

“…However, when conducted using in vivo chromatin, the results of this procedure will reflect not only the inherent sequence preferences of the histone octamer, but also the action of the plethora of other biological factors influencing both nucleosome occupancy and positioning. Even if conducted on nucleosomes reconstituted in vitro, the imprecision and biases in cutting by the MNase will have a significant impact (Jin et al, 2018). Moreover, the result for a given stretch of genomic sequence will always also be influenced by the nucleosome binding properties of the surrounding sequence and corresponding steric hindrance effects.…”

“…Owing to the double helical nature of DNA, the same face contacts the histone complex every ten to eleven base pairs; nucleosome formation is thus facilitated by the periodical occurrence of alternatingly flexible (like AT, AA, or TT) and stiff (like GC) dinucleotide steps (kink-and-slide model) (Vasudevan et al, 2010). In addition, it is believed that the presence of short homopolymeric stretches of deoxyadenosine nucleotides referred to as poly(dA:dT) or dA:dT tracks, which are intrinsically stiff and are frequently found in nucleosomedepleted regions, impedes nucleosome formation (Jin et al, 2018;. Overall, much effort has been devoted in recent years to characterize nucleosome sequence preferences in vitro Segal et al, 2006) and in vivo (Jin et al, 2018;Kaplan et al, 2010) and to predict nucleosome positions in the genome on this basis (Segal et al, 2006;Tillo et al, 2010).…”

“…In addition, it is believed that the presence of short homopolymeric stretches of deoxyadenosine nucleotides referred to as poly(dA:dT) or dA:dT tracks, which are intrinsically stiff and are frequently found in nucleosomedepleted regions, impedes nucleosome formation (Jin et al, 2018;. Overall, much effort has been devoted in recent years to characterize nucleosome sequence preferences in vitro Segal et al, 2006) and in vivo (Jin et al, 2018;Kaplan et al, 2010) and to predict nucleosome positions in the genome on this basis (Segal et al, 2006;Tillo et al, 2010). However, the precise degree to which the underlying sequence directs nucleosome positioning, and which sequence features are most important, is still a matter of debate (Jin et al, 2018;Kaplan et al, 2010;Struhl and Segal, 2013;Zhang et al, 2009).…”

“…Overall, much effort has been devoted in recent years to characterize nucleosome sequence preferences in vitro Segal et al, 2006) and in vivo (Jin et al, 2018;Kaplan et al, 2010) and to predict nucleosome positions in the genome on this basis (Segal et al, 2006;Tillo et al, 2010). However, the precise degree to which the underlying sequence directs nucleosome positioning, and which sequence features are most important, is still a matter of debate (Jin et al, 2018;Kaplan et al, 2010;Struhl and Segal, 2013;Zhang et al, 2009). This is in part due to the fact that most studies have relied on MNase digestion of genomic DNA followed by deep sequencing and fragment counting to derive nucleosome occupancy values.…”

Epigenetic engineering of yeast reveals dynamic molecular adaptation to methylation stress and genetic modulators of specific DNMT3 family members

“…It is well known that nucleosomal DNA is sometimes enriched for AA/TT dinucleotides with 10.5 bp periodicity and these dinucleotides tend to be positioned in the minor groove facing toward the histone core (45-50), thereby contributing to the rotational positioning of nucleosomes in vivo (46,47).…”