Are nucleosome positions in vivo primarily determined by histone–DNA sequence preferences?

Abstract

Large-scale and genome-wide studies have concluded that ∼80% of the yeast (Saccharomyces cerevisiae) genome is occupied by positioned nucleosomes. In vivo this nucleosome organization can result from a variety of mechanisms, including the intrinsic DNA sequence preferences for wrapping the DNA around the histone core. Recently, a genome-wide study was reported using massively parallel sequencing to directly compare in vivo and in vitro nucleosome positions. It was concluded that intrinsic DNA sequence preferences indeed have a dominant role in determining the in vivo nucleosome organization of the genome, consistent with a genomic code for nucleosome positioning. Some other studies disagree with this view. Using the large amount of data now available from several sources, we have attempted to clarify a fundamental question concerning the packaging of genomic DNA: to what extent are nucleosome positions in vivo determined by histone-DNA sequence preferences? We have analyzed data obtained from different laboratories in the same way, and have directly compared these data. We also identify possible problems with some of the experimental designs used and with the data analysis. Our findings suggest that DNA sequence preferences have only small effects on the positioning of individual nucleosomes throughout the genome in vivo.

Sequence-based prediction of single nucleosome positioning and genome-wide nucleosome occupancy

“…The remarkably large apparent role of DNA sequence in organizing nucleosome positions in vivo has led to a lively debate about the methodology used to obtain genome-wide nucleosome maps (25). Part of this discussion focuses on the role of the known sequence preference of micrococcal nuclease (MNase), which is difficult to disentangle from nucleosomal sequence preferences.…”

“…Although DNA sequence appears to strongly influence histoneoctamer binding, the DNA sequence does not appear to encode the distance between adjacent bound histone octamers observed with in vivo assembled chromatin (25). In order to maintain a controlled distribution of distances, nucleosomes need to be repositioned, most likely by ATP-dependent chromatin-remodeling enzymes such as ACF and CHD1 (65)(66)(67)(68)(69).…”

“…Shortly after this study, Zhang et al (24) reported a similar study on in vivo and in vitro assembled yeast chromatin, but using a somewhat different methodology. They and others (24,25) concluded that intrinsic histone-DNA interactions are not the major determinant of nucleosome positioning, but rather of nucleosome occupancy. Positioning and occupancy of nucleosomes are closely related concepts; nucleosome positioning is the distribution of individual nucleosomes along the DNA sequence and can be thought of in terms of a single reference point on the nucleosome, such as its dyad of symmetry (9,26).…”

Nucleosome Positioning in Saccharomyces cerevisiae

“…Technical and methodological issues concerning both studies have been the subject of an ongoing debate (78,79,136,162,210,211). Whereas no con-sensus has been reached, some differences might be explained by the different methods employed by both groups.…”

Nucleosome positioning in a model of active chromatin remodeling enzymes

“…To a first approximation, chromatin can be considered as a linear array of nucleosomes, and a body of experimental evidence indicates that primary DNA sequence controls the position of at least a fraction of nucleosomes: Histone-DNA affinities vary with sequence over a roughly 8 k B T range (2). Nevertheless, the overall degree to which nucleosomes are positioned by DNA sequence is a subject of ongoing debate (3)(4)(5). Transcription, replication, recombination, and DNA repair all need access to bare DNA and hence the organization of nucleosomes must be accomplished in a way that allows rapid, localized access to DNA (6).…”