Histone chaperone networks shaping chromatin function

Abstract

The association of histones with specific chaperone complexes is important for their folding, oligomerization, post-translational modification, nuclear import, stability, assembly and genomic localization. In this way, the chaperoning of soluble histones is a key determinant of histone availability and fate, which affects all chromosomal processes, including gene expression, chromosome segregation and genome replication and repair. Here, we review the distinct structural and functional properties of the expanding network of histone chaperones. We emphasize how chaperones cooperate in the histone chaperone network and via co-chaperone complexes to match histone supply with demand, thereby promoting proper nucleosome assembly and maintaining epigenetic information by recycling modified histones evicted from chromatin.

Figure 1. Overview of histone deposition mechanisms

Newly synthesized histones are incorporated into chromatin via globally and locally acting mechanisms. A network of specialized histone chaperones controls histone delivery and deposition. The figure provides an overview of replication-coupled and replication-independent pathways that require the incorporation of newly synthesized canonical histones and replacement variants, together with parental histone recycling. The histone chaperones that are implicated in each process are listed; for definitions of histone chaperone abbreviations see TABLE 1.

Figure 2. Structural features of histone–chaperone complexes

Two-dimensional depictions of 3D structures in the RCSB Protein Data Bank (PDB). Protein secondary structures are represented by arrows (β-strands), rectangles (α-helices) and black lines (loops). In some cases, loops are represented as a thick line and free DNA-interaction surfaces are indicated by a broken line. For definitions of histone chaperone abbreviations see TABLE 1. A. Histone chaperones binding dimeric H3–H4: (part Aa) Asf1–H3–H4 (PDB identifier: 2HUE); (part Ab) HJURP–CENP-A–H4 (PDB ID: 3R45); (part Ac) Scm3–Cse4–H4 (PDB ID: 2YFV); and (part Ad) DAXX–H3.3–H4 (PDB ID: 4H9N), the location of the nucleosomal H3 αN helix (PDB ID: 1AOI) is indicated by broken lines. B. Histone chaperones binding tetrameric H3–H4: (part Ba) MCM2–H3–H4 (PDB ID: 5BNV) — note that the structure includes two MCM2 HBDs; (part Bb) SPT2–H3–H4 (PDB ID: 5BSA); and (part Bc) SPT16 middle domain (SPT16-M)–H3–H4 (PDB ID: 4Z2M). C. Histones chaperones binding dimeric H2A– or H2A.Z–H2B: (part Ca) Nap1–H2A–H2B (PDB ID: 5G2E); (part Cb) minimal binding domain (MBD) of ANP32E (PDB ID: 4CAY, 4NFT)^, and Swr1 (PDB ID: 4M6B) with a H2A.Z–H2B chimaera (H2A.Z αC helix extension indicated), and SPT16 with H2A–H2B (PDB ID: 4WNN); (part Cc) SPT16-M–H2B chimaera with H2A (PDB ID: 4KHA); (part Cd) YL1 in complex with H2A.Z–H2B (PDB ID: 5FUG, 5CHL)^,; and (part Ce) Chz1–H2A.Z–H2B (PDB ID: 2JSS). D. Co-chaperone complexes: (part Da) MCM2–Asf1 chimaera bound to H3–H4 (PDB ID: 5BO0); (part Db) the Vps75–Asf1–H3–H4 co-chaperone complex; (part Dc) UBN1–H3.3–H4–Asf1 (PDB ID: 4ZBJ); and (part Dd) MCM2-TONSL bound to a H3–H4 tetramer (PDB ID: 5JA4).

Figure 3. Other histone chaperone structures

Two-dimensional depictions of 3D structures in the RCSB Protein Data Bank (PDB). Histone chaperones are shown in yellow. For definitions of histone chaperone abbreviations see TABLE 1. A | Immunoglobulin-like folds: (part Aa) Asf1 (PDB identifier: 1ROC), showing the location of B-domain interactions with Rad53 (PDB ID:2YGV), Cac2/CAF1 p60 (PDB ID: 2Z3F), Hip1/Hir1/HIRA (PDB ID: 2Z34, 2I32)^, and codanin 1 (REF. 96); and (part Ab) the YEATS domain of Yaf9 (PDB ID: 3FK3). B | Tetratricopeptide repeat of Hif1 (PDB ID: 4NQ0). C | Tandem pleckstrin homology domains (PH1 and PH2) of Rtt106 (PDB ID: 3GYP). D | Nucleosome assembly protein 1 (Nap1)-like folds of (part Da) the Nap1 dimer (PDB ID: 2AYU); (part Db) Vps75 tetramer (PDB ID: 5AGC); and Vps75–Rtt109 complexes with (part Dc) 2:1 (PDB ID: 3Q66) and (part Dd) 2:2 (PDB ID: 3Q35) stoichiometries. E | Nucleoplasmin (NPM) fold of Xenopus laevis NO38 (PDB ID: 1XB9). F | WD40 repeat domains of RBAP46 and RBAP48 proteins with the H4 α1 (PDB ID: 3C9C, 3CFV)^, and the H3 tail (PDB ID: 2YBA).

Figure 4. The histone supply network

After synthesis, histones H3–H4 and H2A–H2B engage with multiple different chaperones and enzymes on their way to chromatin. ASF1 is a central chaperone in the delivery of newly synthesized H3.1–, H3.2– or H3.3–H4 dimers. Histone-free ASF1 is phosphorylated by tousled-like kinases (TLKs), promoting histone binding. Histones bound by ASF1 are engaged in multiple different co-chaperone complexes, which further shields their functional interfaces and facilitates their acetylation, nuclear import and storage. Co-chaperoning may be a general paradigm, supporting branching of the pathway and the modification of histones ‘on the go’. ASF1 shuttles H3.1/H3.2–H4 and H3.3–H4 dimers to the CAF1 and HIRA complexes for replication-coupled and replication-independent deposition, respectively. H3.3–H4 dimers are also deposited by DAXX–ATRX, whereas the H2A–H2B supply is handled by NAP1 and FACT. Histone chaperones also have an important role in the feedback regulation of histone supply. Although several histone chaperones are implicated in H3–H4 delivery with ASF1, it is still unclear whether other chaperones collaborate with DAXX and NAP1 in the delivery of H3.3–H4 and H2A–H2B dimers, respectively. See TABLE 1 for definitions of histone chaperone abbreviations.

Figure 5. Recruitment of histone chaperones to chromatin

Histone chaperones recognize specific factors or features of chromatin to target canonical and variant histones to designated genomic loci. The CAF1 complex binds to PCNA to promote deposition during DNA replication (part a) and DNA repair (part b), whereas the HIRA complex may be recruited by naked DNA (part b). At transcription start sites (TSSs), Swr1 as part of the SWR-C complex recognizes the nucleosome-depleted region and exchanges H2A–H2B for H2A.Z–H2B at the −1 and +1 nucleosome (part c). Furthermore, the HIRA complex interacts with RNA polymerase II (Pol II) and transcription factors, which could facilitate H3.3–H4 deposition in gene bodies and at promoters, respectively. SPT2, SPT6 and potentially Vps75 mediate recycling of H3–H4 during ongoing transcription and SPT6 can be recruited by binding the phosphorylated carboxy-terminal repeat domain of Pol II. NAP1 and FACT are also recruited to transcription sites and can facilitate histone H2A–H2B eviction. In heterochromatin (telomeres, pericentromeres and repetitive elements), DAXX–ATRX is recruited through ATRX-mediated binding to H3K9me3 (part d). At centromeres, HJURP recruitment requires priming by the MIS18 complex together with core centromeric components (part e). For definitions of histone chaperone abbreviations, see TABLE 1.

Figure 6. Parental histone recycling during DNA replication

Evicted parental histones are randomly segregated to daughter DNA strands. The FACT complex may contribute to nucleosome disruption and histone recycling through interaction with the CMG complex (which includes CDC45–MCM2–7–GINS), polymearase α(polα) and RPA. MCM2, which is part of the CMG helicase complex, provides a binding platform for evicted H3–H4 tetramers and may facilitate their recycling directly or in collaboration with FACT or as dimers with ASF1, which splits H3–H4 tetramers and forms a co-chaperone complex with MCM2. It remains unknown whether other components of the DNA replication machinery have histone chaperone activity and whether deposition of old and new histones occurs by separate pathways. For definitions of histone chaperone abbbreviations, see TABLE 1.