The right place at the right time: chaperoning core histone variants

Abstract

Histone proteins dynamically regulate chromatin structure and epigenetic signaling to maintain cell homeostasis. These processes require controlled spatial and temporal deposition and eviction of histones by their dedicated chaperones. With the evolution of histone variants, a network of functionally specific histone chaperones has emerged. Molecular details of the determinants of chaperone specificity for different histone variants are only slowly being resolved. A complete understanding of these processes is essential to shed light on the genuine biological roles of histone variants, their chaperones, and their impact on chromatin dynamics.

Keywords: chromatin dynamics; histone chaperones; histone variants; nucleosome.

Figure 1. Canonical and variant nucleosomes

(A) Elements of the histone fold and structures of Xenopus leavis H2A–H2B, H3–H4 and (H3–H4)₂ (PDB ID: 1KX5). (B) Structure of the canonical Xenopus leavis nucleosome (PDB ID: 1KX5). Other nucleosome structures, such as the human nucleosome, are structurally similar. (C) Structure of the CenH3^CENP-A-containing nucleosome (PDB ID: 3AN2). (D) Zoomed view of the αN helix of CenH3^CENP-A (left) and H3 (right) involved in stabilizing the DNA ends. Histone H3 is blue, CenH3^CENP-A is cyan, H4 is green, H2A is yellow, H2B is red, and DNA is white

Figure 2. Schematic of select H3 and H2A variants

Schematic representation of select human H3 (A) and H2A (B) variants and the yeast homologs. The histone fold is shown in solid blue shades for H3 isoforms and in orange shades for H2A isoforms. The tails are shown as lines. Specific amino acid substitutions are reported. Different shades of color are used to indicate the degree of sequence divergence. Residues involved in forming the acidic patch on H2A isoforms are shown in red (where the acidic residues are present) and white (for H2A.B which lacks these residues). Sequence identity to the human canonical histone is shown in gray.

Figure 3. Structures of H3 variants and their chaperones

(A) Structure of the H3-H4 (PDB ID: 1KX5) and of the complex with the histone-binding domain of ASF1 (PDB ID: 2HUE). (B) Structure of CenH3^CENP-A-H4 and of the complex with the histone-binding domain of HJURP (PDB ID: 3R45) and Scm3 (PDB: 2YFV). The CATD domain of CenH3 is orange. (C) Structure of H3.3–H4 and of the complex with the histone-binding domain of DAXX (PDB ID: 4H9N). Shown in orange are the H3.3-specific residues, with G90 shown as spheres. (D) Zoomed view of the DAXX Glu225 and H3.3 Gly90 interface, the key determinant for specificity in vivo. (E) Structure of H3.3–H4 with the histone-binding peptide of UBN1 and ASF1 (PDB ID: 4ZBJ). Shown in orange are the H3.3-specific residues, with G90 shown as spheres. In all panels, H3 isoforms are blue, CenH3 is cyan, H4 is green, and ASF1 is gold. Specific chaperones HJURP, Scm3, UBN1, and DAXX are shown in maroon.

Figure 4. Structures of H2A variants and their chaperones

(A) Structure of H2A-H2B (PDB ID: 1KX5) and of the complex with the histone-binding domain of the chaperone FACT (PDB ID: 4KHA). (B) Structure of H2A.Z–H2B and of the complex with the histone-binding region of Chz1 (PDB ID: 2JSS). (C) Structure of the complex between the Swr1 histone-binding region and the H2A.Z–H2B dimer (PDB ID: 4M6B). (D) Superposition of the H2A–H2B and H2A.Z–H2B dimers, close up view on the αC helix which is extended in H2A.Z due to a single amino acid deletion. (E) Structure of the ANP32E histone-binding region–H2A.Z–H2B complex (PDB ID: 4CAY). Shown in dark green is the region of the αC helix important for H2A.Z specificity. H2A is yellow, H2A.Z is gold, H4 is red, and FACT is light blue. Chaperones Chz1, Swr1, and ANP32E are purple.