The mechanics behind DNA sequence-dependent properties of the nucleosome

Abstract

Chromatin organization and composition impart sophisticated regulatory features critical to eukaryotic genomic function. Although DNA sequence-dependent histone octamer binding is important for nucleosome activity, many aspects of this phenomenon have remained elusive. We studied nucleosome structure and stability with diverse DNA sequences, including Widom 601 derivatives with the highest known octamer affinities, to establish a simple model behind the mechanics of sequence dependency. This uncovers the unique but unexpected role of TA dinucleotides and a propensity for G|C-rich sequence elements to conform energetically favourably at most locations around the histone octamer, which rationalizes G|C% as the most predictive factor for nucleosome occupancy in vivo. In addition, our findings reveal dominant constraints on double helix conformation by H3–H4 relative to H2A–H2B binding and DNA sequence context-dependency underlying nucleosome structure, positioning and stability. This provides a basis for improved prediction of nucleosomal properties and the design of tailored DNA constructs for chromatin investigations.

Principles and practice of nucleosome positioningin vitro

“…The consequence of more interactions being made between DNA and H3-H4 is that the region of DNA inside SHL ±3.5 dominates DNA sequence effects on positioning and stability. It has been proposed that the energetic significance of contact points can be ranked in descending order: SHL 1.5 > 2.5 > 0.5 > 3.5 > 4.5 > 5.5 (Chua et al 2012).…”

“…The scaffold of interaction surfaces provided by histones make up the set of 14 SHL contact points (Figures 4c and 4d) or 'binding platforms' (Chua et al 2012). Each induces a set of responses in the wrapped DNA conformation, which have been analysed in detail (Richmond and Davey 2003;Olson and Zhurkin 2011;Chua et al 2012).…”

“…Each induces a set of responses in the wrapped DNA conformation, which have been analysed in detail (Richmond and Davey 2003;Olson and Zhurkin 2011;Chua et al 2012).…”

“…The energetics of these deformations gives rise to sequence specific effects on DNA binding, and many authors have addressed the question of how they are linked with choice of nucleosome position (see Segal and Widom 2009a;Travers et al 2009;Radman-Livaja and Rando 2010;Olson and Zhurkin 2011;Trifonov 2011;Zhurkin 2011;Chua et al 2012).…”

“…It is important to note that although the least energetic cost of deformations is seen in TA base step stacking energy and A/T base pairs, and can be used to enable the required DNA conformation, sequences containing G/C base pairs can nevertheless be integrated in a histone-DNA contact point (Chua et al 2012).…”