Histone chaperones, histone acetylation, and the fluidity of the chromogenome

Abstract

The "chromogenome" is defined as the structural and functional status of the genome at any given moment within a eukaryotic cell. This article focuses on recently uncovered relationships between histone chaperones, post-translational acetylation of histones, and modulation of the chromogenome. We emphasize those chaperones that function in a replication-independent manner, and for which three-dimensional structural information has been obtained. The emerging links between histone acetylation and chaperone function in both yeast and higher metazoans are discussed, including the importance of nucleosome-free regions. We close by posing many questions pertaining to how the coupled action of histone chaperones and acetylation influences chromogenome structure and function.

Figure 1. A Schematic Model depicting the chromogenomes of two distinct cells

Both cells express housekeeping genes (green), with similar chromatin structure and post-translational, or chromogenetic, modifications. Each cell also expresses specific genes that confer a unique tissue-specific phenotype (red) or response to an environmental stimulus (blue). Nucleosomal histones associated with the rapid-response gene undergo rapid and reversible acetylation, enabling an immediate response to specific stimuli. As such, the highly reversible nature of these chromatin changes are not considered epigenetic, as they are not transmitted to daughter cells.

Figure 2. The different histone chaperone families have completely different tertiary and quaternary structures

Structures are displayed in ribbon diagrams, using Pymol. Histones H2A, H2B, H3 and H4 are colored in pastel yellow, red, blue and green, respectively. Single chaperone subunits are colored in red, the second subunit in the Nap1 homodimer is colored in blue. Nucleophosmin is a pentamer of five identical subunits. Details and references are given in supplementary table 1.

Figure 3. Structural comparison of Nap1 family members

All Nap1 family members are obligatory dimers (as seen in Fig. 1a). For ease of comparison, only one chain is shown here. Yeast Nap1 (ScNap1) was submitted to Dali. Yeast Vps75 (ScVps75 and human Set (hsSet) were the two top hits. ScVps75: rmsd = 3.7, Z-score = 12.6, length of alignment = 181, no. res = 205, %id = 14. HsSet: rmsd = 2.5, Z-score = 14.8, length of alignment = 166, no. res = 167, %id = 25. a. ScNap1; Chain A (PDB 2Z2R Residues 82-365) b. ScVps75; Chain B (PDB 3DM7; Residues 12-222) c. hSET; Chain B (PDB 2E50; Residues 24-221)

Figure 4. Acetylation sites are located on the histone tails and on the structured regions

The structure of the nucleosome (1aoi) is displayed in ribbon format; histone tails have been extended to their approximate length since they are largely disordered in the crystal structure. Dots indicate lysine residues known to be acetylated.

Figure 5. Protein-protein interaction maps for several histone chaperones

The red oval indicates the approximate location of HATs within the maps. Generated using evidence view, with a required confidence of 0.50; custom limit 150. http://string.embl.de. Different line colors represent the types of evidence for the association.

Figure 6. Model of Acetylation-Dependent Nucleosome Eviction by Nap1

The binding of transcriptional activators (Tax/CREB) is required for the recruitment of the coactivator and HAT, p300, to the chromatin-assembled model promoter. In the presence of acetyl CoA (Ac-CoA), p300 acetylates the histone H3 tail; a requirement for Nap1-mediated disassembly of nucleosome octamers. Nucleosome eviction exposes the promoter DNA for the binding of the preinitiation complex.