Limits...
The mechanics behind DNA sequence-dependent properties of the nucleosome.

Chua EY, Vasudevan D, Davey GE, Wu B, Davey CA - Nucleic Acids Res. (2012)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Structural and Computational Biology, School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.

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.

Show MeSH
Constraints of histone binding on double helix structure and site-dependent variation between different DNA sequences. (A–D) The structures of NCP147 (magenta), NCP146b (yellow) and NCP-601L (cyan) were superimposed via the histone-fold regions of the octamer (DNA binding motifs: L, loop, A, α-helix). The phosphorous atoms of the binding platforms appear as large spheres, and water molecules mediating a conserved DNA–histone hydrogen bond bridge are shown with small spheres (A and C; CWB). (A and C) H3–H4 tetramer binding sites. (B and D) H2A–H2B dimer binding sites.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3401446&req=5

gks261-F5: Constraints of histone binding on double helix structure and site-dependent variation between different DNA sequences. (A–D) The structures of NCP147 (magenta), NCP146b (yellow) and NCP-601L (cyan) were superimposed via the histone-fold regions of the octamer (DNA binding motifs: L, loop, A, α-helix). The phosphorous atoms of the binding platforms appear as large spheres, and water molecules mediating a conserved DNA–histone hydrogen bond bridge are shown with small spheres (A and C; CWB). (A and C) H3–H4 tetramer binding sites. (B and D) H2A–H2B dimer binding sites.

Mentions: Previous models for the sequence-dependent mechanics of wrapping in the nucleosome have been based on the contribution of specific DNA conformational parameters, foremost base pair step roll and slide (Figure 3A for an illustration of the six dinucleotide step parameters), towards generation of the superhelix (5,32). However, this is only an indirect description that does not address the underlying localized constraints on double helix structure, which moreover arise from a form of protein association that is unique to the nucleosome. Histone binding involves mainly interaction with the inward-facing phosphodiester backbone. In particular, for every turn of the double helix there are four phosphate groups that are in closest proximity to the histone octamer surface, encompassing the most extensive protein–DNA interactions. The phosphorus atoms of these four phosphate groups, designated as the ‘binding platform’, lie roughly in a plane and show the least variation in position between different DNA sequences (Figures 1A and 5). Thus, the binding platform represents the most constraining feature of histone association, which requires a very narrow minor groove for both DNA strands to fit on the protein surface. Correspondingly, the major groove must be narrow where it faces inward in order for both strands to fit onto adjacent binding platforms. Furthermore, the two sides of the binding platforms each act like a ‘hinge’, which allows freedom in the positioning of the opposing, unbound DNA strand (Figures 1A, 5 and 6). This attribute permits substantial conformational variation between different DNA sequences, limiting the sequence dependency of the nucleosomal system.Figure 5.


The mechanics behind DNA sequence-dependent properties of the nucleosome.

Chua EY, Vasudevan D, Davey GE, Wu B, Davey CA - Nucleic Acids Res. (2012)

Constraints of histone binding on double helix structure and site-dependent variation between different DNA sequences. (A–D) The structures of NCP147 (magenta), NCP146b (yellow) and NCP-601L (cyan) were superimposed via the histone-fold regions of the octamer (DNA binding motifs: L, loop, A, α-helix). The phosphorous atoms of the binding platforms appear as large spheres, and water molecules mediating a conserved DNA–histone hydrogen bond bridge are shown with small spheres (A and C; CWB). (A and C) H3–H4 tetramer binding sites. (B and D) H2A–H2B dimer binding sites.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3401446&req=5

gks261-F5: Constraints of histone binding on double helix structure and site-dependent variation between different DNA sequences. (A–D) The structures of NCP147 (magenta), NCP146b (yellow) and NCP-601L (cyan) were superimposed via the histone-fold regions of the octamer (DNA binding motifs: L, loop, A, α-helix). The phosphorous atoms of the binding platforms appear as large spheres, and water molecules mediating a conserved DNA–histone hydrogen bond bridge are shown with small spheres (A and C; CWB). (A and C) H3–H4 tetramer binding sites. (B and D) H2A–H2B dimer binding sites.
Mentions: Previous models for the sequence-dependent mechanics of wrapping in the nucleosome have been based on the contribution of specific DNA conformational parameters, foremost base pair step roll and slide (Figure 3A for an illustration of the six dinucleotide step parameters), towards generation of the superhelix (5,32). However, this is only an indirect description that does not address the underlying localized constraints on double helix structure, which moreover arise from a form of protein association that is unique to the nucleosome. Histone binding involves mainly interaction with the inward-facing phosphodiester backbone. In particular, for every turn of the double helix there are four phosphate groups that are in closest proximity to the histone octamer surface, encompassing the most extensive protein–DNA interactions. The phosphorus atoms of these four phosphate groups, designated as the ‘binding platform’, lie roughly in a plane and show the least variation in position between different DNA sequences (Figures 1A and 5). Thus, the binding platform represents the most constraining feature of histone association, which requires a very narrow minor groove for both DNA strands to fit on the protein surface. Correspondingly, the major groove must be narrow where it faces inward in order for both strands to fit onto adjacent binding platforms. Furthermore, the two sides of the binding platforms each act like a ‘hinge’, which allows freedom in the positioning of the opposing, unbound DNA strand (Figures 1A, 5 and 6). This attribute permits substantial conformational variation between different DNA sequences, limiting the sequence dependency of the nucleosomal system.Figure 5.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Structural and Computational Biology, School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.

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.

Show MeSH