Variation on a theme: Evolutionary strategies for H2A.Z exchange by SWR1-type remodelers
Introduction
At the heart of the nucleosome, the basic unit of chromatin, histone proteins provide both a scaffold and a regulatory surface around which DNA is coiled. Two copies of four conserved ‘canonical’ histones are generally found within the nucleosome: H2A, H2B, H3, and H4 [1]. Across the eukaryotic domain, however, nucleosomes containing ‘variants’ of these histones are present and, in some cases, constitute a significant fraction of the total nucleosomal pool. For all canonical histones at least one variant is known, although the rare H4 variants only occur in some species. Variant histones show significant sequence similarity with their canonical prototypes, but with some variation. For example, while H2A and its variant H2A.X share ∼80% homology, the H3 variant CenH3 is only ∼50–60% identical to its canonical counterpart. During evolution, the sequences of some histone variants (such as H3.3) have been conserved over large time spans, suggesting a highly useful regulatory invention. By contrast, the centromeric CenH3 variant is an example for a rather fast-evolving variant that is adapted to the specific requirements of centromere organization from yeast to humans [2].
The sequence variations, sometimes extensive or limited to a few amino acids, alter the properties of the nucleosome core particle or provide binding sites for regulators and therefore change chromatin structure locally [3]. Accordingly, histone variants regulate all processes that involve nucleosomal substrates: gene expression, DNA replication, chromosome segregation, and DNA repair [2, 3, 4].
Because histone variants implement local chromatin structure modifications, mechanisms of their placement are of considerable interest. Histone variants are generally introduced into nucleosomes by exchange with their canonical counterparts, and, depending on the variant and species, this process requires dedicated histone chaperones, ATP-dependent nucleosome remodeling factors, or even a combination of both [3,5]. Nucleosome disruption by polymerases during transcription and replication may also provide windows of opportunity for exchange [6,7].
In this review, we summarize recent discoveries on the role and regulation of the conserved histone H2A variant H2A.Z. We also highlight how different evolutionary strategies, involving site-specific incorporation of this variant through ATP-dependent remodeling complexes, expand the potential for chromatin regulation.
Section snippets
The H2A.Z variant
The H2A variant H2A.Z is considered a ‘universal’ variant, as it can be found in virtually all eukaryotes [2]. H2A.Z is highly conserved, even more than the canonical H2A, suggesting that it arose early, and only once, during evolution [8]. In addition, this variant is one of the most abundant ones, as in both flies [9] and mammals [8] it is present in ∼5–10% of nucleosomes. A comparison between H2A and H2A.Z shows ∼60% homology (depending on the organism), with differences predominantly
H2A.Z in transcription (and beyond)
With the notable exception of yeast, in which knockout of Htz1 (coding for H2A.Z) causes growth defects but not lethality [15], H2A.Z is essential in other organisms, such as mice, flies, and worms [16]. This lethal phenotype may be explained by the involvement of H2A.Z in the regulation of gene expression programs. Indeed, in several cases, depletion of H2A.Z causes significant transcriptional perturbations (reviewed in the study by Giaimo et al. [16]). This statement may only apply to
Incorporation and removal of H2A.Z
H2A.Z clearly regulates chromatin-based processes, but how, in turn, is H2A.Z regulated? In yeast, H2A.Z is incorporated into nucleosomes by the ATP-dependent chromatin remodeling complex SWR1 (SWR1.C) [18]. The catalytic subunit of this complex, SWR1, is a Snf2 (SF2) helicase of the INO80 subfamily. The mechanism of H2A.Z incorporation by SWR1.C (reviewed in the study by Willhoft and Wigley [46]) has been thoroughly investigated with years of biochemistry [18,35,47, 48, 49], which culminated
SWR1 remodelers meet NuA4 acetyltransferases
The localization of H2A.Z at promoters places it in the context of active histone marks, such as acetylation. Interestingly, this potential synergy between histone variants and modification to regulate transcription seems to be reflected by physical links between SWR1-type remodelers and the histone acetyltransferase complex NuA4 — with remarkable evolutionary variation.
Of the 14 subunits that make up the yeast SWR1.C, four are also present within NuA4.C (Figure 3A). The NuA4 complex catalyzes
Conclusions
While providing interesting new insights into H2A.Z, the recent literature brings in a new wave of mysteries and controversies. Despite the ‘universal’ conservation of H2A.Z and its properties, the function of this variant is still hard to generalize across different organisms. This may be due to the context-dependent modulation of H2A.Z function, which is hard to resolve by current methodology.
The same applies to remodeling enzymes dedicated to H2A.Z. They nicely illustrate how different
Conflict of interest statement
Nothing declared.
Acknowledgement
This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Council) — Project ID 213249687 – SFB1064-A1.
References (62)
Histone H2A variants H2AX and H2AZ
Curr Opin Genet Dev
(2002)Quantification of proteins and histone marks in Drosophila embryos reveals stoichiometric relationships impacting chromatin regulation
Dev Cell
(2019)- et al.
H2A.Z: view from the top
Structure
(2008) Drosophila SWR1 and NuA4 complexes are defined by DOMINO isoforms
eLife
(2020)Znhit1 controls intestinal stem cell maintenance by regulating H2A.Z incorporation
Nat Commun
(2019)EP400 deposits H3.3 into promoters and enhancers during gene activation
Mol Cell
(2016)- et al.
The role of histone H2Av variant replacement and histone H4 acetylation in the establishment of Drosophila heterochromatin
Genes Dev
(2005) Histone variants H2A.Z and H3.3 coordinately regulate PRC2-dependent H3K27me3 deposition and gene expression regulation in mES cells
BMC Biol
(2018)VPS72/YL1-Mediated H2A.Z deposition is required for nuclear reassembly after mitosis
Cells
(2020)Structure and dynamics of the yeast SWR1-nucleosome complex
Science
(2018)
A histone acetylation switch regulates H2A.Z deposition by the SWR-C remodeling enzyme
Science
Single amino acid change underlies distinct roles of H2A.Z subtypes in human Syndrome
Cell
Merge and separation of NuA4 and SWR1 complexes control cell fate plasticity in Candida albicans
Cell Discov
MEGA X: molecular evolutionary genetics analysis across computing platforms
Mol Biol Evol
Crystal structure of the nucleosome core particle at 2.8 A resolution
Nature
Histone variants--ancient wrap artists of the epigenome
Nat Rev Mol Cell Biol
Old cogs, new tricks: the evolution of gene expression in a chromatin context
Nat Rev Genet
The histone code at DNA breaks: a guide to repair?
Nat Rev Mol Cell Biol
Histone variants in pluripotency and disease
Development
Centromere transcription allows CENP-A to transit from chromatin association to stable incorporation
J Cell Biol
Centromere and pericentromere transcription: roles and regulation ... in sickness and in health
Front Genet
The variant histone H2A.V of Drosophila--three roles, two guises
Chromosoma
Crystal structure of a nucleosome core particle containing the variant histone H2A.Z
Nat Struct Biol
Crystal structures of heterotypic nucleosomes containing histones H2A.Z and H2A
Open Biol
The essential histone variant H2A.Z regulates the equilibrium between different chromatin conformational states
Nat Struct Biol
Histone H2A.Z has a conserved function that is distinct from that of the major H2A sequence variants
Nucleic Acids Res
The histone variant H2A.Z in gene regulation
Epigenet Chromatin
H2A.Z is dispensable for both basal and activated transcription in post-mitotic mouse muscles
Nucleic Acids Res
ATP-driven exchange of histone H2AZ variant catalyzed by SWR1 chromatin remodeling complex
Science
The SWR1 histone replacement complex causes genetic instability and genome-wide transcription misregulation in the absence of H2A.Z
PLoS One
The histone variant H2A.Z in yeast is almost exclusively incorporated into the +1 nucleosome in the direction of transcription
Nucleic Acids Res
Cited by (14)
The Dynamics of Histone Modifications during Mammalian Zygotic Genome Activation
2024, International Journal of Molecular SciencesActin-related protein 6 facilitates proneural protein-induced gene activation for rapid neural differentiation
2023, Development (Cambridge)PMT6 Is Required for SWC4 in Positively Modulating Pepper Thermotolerance
2023, International Journal of Molecular Sciences
- a
Lead Contact.