Abstract
Nucleosomes represent the fundamental repeating unit of eukaryotic DNA, and comprise eight core histones around which DNA is wrapped in nearly two superhelical turns. Histones do not have the intrinsic ability to form nucleosomes; rather, they require an extensive repertoire of interacting proteins collectively known as ‘histone chaperones’. At a fundamental level, it is believed that histone chaperones guide the assembly of nucleosomes through preventing non-productive charge-based aggregates between the basic histones and acidic cellular components. At a broader level, histone chaperones influence almost all aspects of chromatin biology, regulating histone supply and demand, governing histone variant deposition, maintaining functional chromatin domains and being co-factors for histone post-translational modifications, to name a few. In this essay we review recent structural insights into histone-chaperone interactions, explore evidence for the existence of a histone chaperoning ‘pathway’ and reconcile how such histone-chaperone interactions may function thermodynamically to assemble nucleosomes and maintain chromatin homeostasis.
Highlights
Eukaryotes package their genome within the confines of the cell nucleus into a structure broadly defined as chromatin
Core histones have a set of dedicated molecular chaperones that associate tightly with them from synthesis to chromatin incorporation
Structural biology is spreading ever more light on the molecular details of histone–histone–chaperone interactions. To date this has been predominantly limited to individual domains, yet with the revolution in cryo-electron microscopy we anticipate greater understanding at the larger complex level in the near future
Summary
Eukaryotes package their genome within the confines of the cell nucleus into a structure broadly defined as chromatin. Taking histones H3 and H4 as examples, this has resulted in a number of common themes: (1) Histones are imported through interaction with importin-β proteins, namely IPO4, (2) a multi-chaperoning complex involving ASF1a/b, NASP, HAT1 and RbAp46 forms the major soluble pool of H3 and H4, (3) ASF1 is a central hub for the histone chaperoning network and is regulated by a number of co-chaperoning factors including the Tousled-like kinases 1 and 2 (TLK1 and TLK2), and Codanin-1 (CDAN1) in humans, and (4) H3–H4 are transferred to variant specific chaperones, often tethered to chromatin, for incorporation at sites of DNA replication or histone turnover (Figures 2 and 3). The H3.3 variant accumulates on actively transcribed genes, and over largely silenced regions such as telomeres and pericentromeric regions [103] This observation led to the discovery of the histone-binding protein DAXX and chromatin remodeler ATRX, that form a dimeric complex involved in H3.3 deposition and remodelling [23,29]. ATRX/DAXX complex plays a role in maintaining and propagating this repressive chromatin state [130], working as a positive feedback loop
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