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Review
. 2015 Mar 25;115(6):2274-95.
doi: 10.1021/cr500350x. Epub 2014 Nov 26.

Post-translational modifications of histones that influence nucleosome dynamics

Gregory D Bowman  1 , Michael G Poirier
Affiliations
Review

Post-translational modifications of histones that influence nucleosome dynamics

Gregory D Bowman et al. Chem Rev. .
No abstract available

PubMed Disclaimer

Figures

Figure 1
Figure 1
Overview of nucleosome architecture. (A) Illustration of H2A/H2B and H3/H4 heterodimers and how they fit together to form the histone octamer. (B) Face and top view of the nucleosome structure. For this and all subsequent molecular representations of the nucleosome, the high-resolution crystal structure (PDB code 1KX5) was used.
Figure 2
Figure 2
Schematic drawings of the nucleosome, highlighting features that contribute to nucleosome dynamics. (A) Illustration highlighting energetically important contacts within the nucleosome. The DNA entry/exit region (red) has weaker histone–DNA contacts, and the dyad region (blue) has the most energetically important contacts. Superhelical locations (SHLs) indicate the histone surfaces where contact is made with the DNA minor groove. The histone surface underneath the DNA at the dyad, where the major groove faces the histone octamer, is considered SHL-0, and increasing or decreasing values mark each SHL moving from the dyad to the two entry/exit regions. (B) Map of histone residues where post-translational modifications influence nucleosome dynamics.
Figure 3
Figure 3
Types of nucleosome dynamics that can be affected by PTMs. (A) DNA unwrapping transiently exposes protein-binding sites that are buried within the fully wrapped nucleosome. (B) The DNA can slide relative to the histone octamer and nucleosomes can be disassembled to expose DNA-binding sites. With unmodified histones, these structural changes require histone chaperones and chromatin remodeling complexes. Dyad modifications can enhance both sliding and disassembly. (C) Nucleosomes can unwrap with the H2A/H2B heterodimer attached to DNA. This type of structural dynamics could be an initial step for nucleosome disassembly and H2A/H2B exchange and may be accelerated by PTMs at histone–histone interfaces.
Figure 4
Figure 4
View of the nucleosome (1KX5), with H3(K56) and H3(S57) highlighted in yellow. Located under the DNA near the nucleosome entry/exit region, H3(K56ac) increases site exposure by increasing the DNA unwrapping rate, and influences histone chaperone binding, while H3(S57A) substitution interferes with octamer formation and increases H2A/H2B dimer exchange. Close-up view (bottom) shows the two sides of the nucleosome superimposed, with one copy of each histone in color and one copy in gray. In the crystal structure, H3(S57) hydrogen bonds with neighboring H3(E59) (magenta dotted line) and makes van der Waals contacts with carbonyl oxygens of the αN-helix of histone H3 (gray spheres) but is too far to make direct interactions with DNA. Although the neighboring H3(K56) makes a closer approach to DNA, the lysine side chain is too distant to directly hydrogen-bond to the phosphate backbone. The two positions observed for the H3(K56) side chain suggest some mobility, and the small gray spheres highlight the shortest path from the lysine to the closest DNA phosphates.
Figure 5
Figure 5
View of the nucleosome (1KX5), with H3(Y41), H3(R42), and H3(T45) highlighted in yellow. These residues are located right where the DNA enters and exits the nucleosome. Close-up view (bottom) with the two sides of the nucleosome superimposed shows the same rotamers for H3(Y41) and H3(T45) and two different conformations for H3(R42). In this structure, both H3(R42) and H3(T45) make direct hydrogen bonds to the DNA phosphate backbone (magenta dotted lines). Phosphorylation of Y41 or T45 would be expected to cause steric clashes and electrostatic repulsion with the DNA. The direct impact of PTMs at these positions on nucleosome dynamics has yet to be reported, but they are predicted to increase DNA unwrapping on the basis of studies of H3(K56ac).
Figure 6
Figure 6
View of the nucleosome (1KX5), with H3(K36) highlighted in yellow. This residue is located on the H3 tail just outside where the tail enters between the two gyres of DNA at the entry/exit region. Close-up view (bottom) with the two sides of the nucleosome superimposed shows that even the backbone position of H3(K36) differs between the two copies in this structure. Neither copy of H3(K36) has the lysine side chain within direct hydrogen-bonding distance of the DNA backbone. While modification of this residue does not influence DNA unwrapping, the binding of the Phf1 Tudor domain enhances DNA unwrapping and accessibility. This suggests that other histone PTM readers that bind in the entry/exit region may also alter nucleosome unwrapping/rewrapping dynamics.
Figure 7
Figure 7
View of the nucleosome (1KX5), with H4(K77) and H4(K79) highlighted in yellow. These residues are located around SHL ± 3, where histone mutations result in the loss of rDNA silencing (LRS). Close-up view (bottom) with the two sides of the nucleosome superimposed shows that H4(K79) can occupy two different conformations yet still directly hydrogen-bond to the DNA phosphate backbone and that H4(K77) is too distant to directly hydrogen-bond in this structure. Despite their location relatively far from the edge of the nucleosome, acetylation of these two residues increases DNA unwrapping at the entry/exit site, which may underlie their connection to disrupting transcriptional silencing.
Figure 8
Figure 8
View of the nucleosome (1KX5), with H3(K115), H3(T118), H3(K122), and H4(S47) highlighted in yellow. Located around SHL ± 0.5, these residues are positioned within the most energetically important histone–DNA contacts. Close-up view (bottom) with the two sides of the nucleosome superimposed shows very similar conformations for these residues. H3(T118) generates a SIN phenotype when mutated and directly hydrogen-bonds to both the DNA phosphate backbone and another SIN residue, H4(R45) (magenta dotted lines). Phosphorylation of H3(T118), which would likely disrupt these energetically important interactions, has been shown to destabilize the nucleosome, similar to SIN mutations.,,
Figure 9
Figure 9
View of the nucleosome (1KX5), with H3(K64) shown in yellow. Located at SHL ± 2, this position lies underneath the major groove of DNA and would not be easily accessible to a histone-modifying enzyme in a fully wrapped nucleosome. Close-up view (bottom) with the two sides of the nucleosome superimposed shows very different positions of the lysine side chain, neither within hydrogen-bonding distance of the DNA phosphate backbone (gray spheres). From the crystal structure, the manner in which modification of H3(K64) would directly impact nucleosome dynamics is not clear.
Figure 10
Figure 10
View of the nucleosome (1KX5), with H4(K91) and H4(R92) highlighted in yellow. These residues are located near the center of the histone octamer, at the interface between H2A/H2B dimers and H3/H4 tetramer, and are not readily accessible from the exterior of the nucleosome in the crystal structure. In the far view (top), the backbone of H3/H4 on the right side is semitransparent so that H4(R92) can be seen. Close-up view (bottom) with the two sides of the nucleosome superimposed shows that both copies are in very similar conformations, with each making direct hydrogen bonds to residues on H2B (magenta dotted lines). Modification of either H4(K91) or H4(R92) would be expected to interfere with these hydrogen bonds. H4(K91ac) is involved in nucleosome assembly and may increase fluctuations or dissociation of H2A/H2B on the nucleosome.
Figure 11
Figure 11
Changes in nucleosome organization carried out by chromatin remodelers. (A) Most chromatin remodelers can reposition or “slide” nucleosomes along DNA. Depending on the direction of sliding, this repositioning can bury or expose DNA binding sites. Remodelers like Chd1 and many ISWI-type remodelers are sensitive to DNA flanking the nucleosome and generate evenly spaced nucleosome arrays (top). In contrast, other remodelers such as SWI/SNF and RSC can shift nucleosomes into their neighbors, generating dimeric or altosome structures, which are believed to be intermediates for nucleosome disassembly (bottom). The altosome organization depicted here was adapted from a model of Ulyanova and Schnitzler. (B) Some remodelers specialize in histone variant exchange. Exchange of canonical and variant H2A/H2B dimers, highlighted here, is carried out by SWR1 and INO80.
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