Abstract
An expanding repertoire of histone variants and specialized histone chaperone partners showcases the versatility of nucleosome assembly during different cellular processes. Recent research has suggested an integral role of nucleosome assembly pathways in both maintaining cell identity and influencing cell fate decisions during development and normal homeostasis. Mutations and altered expression profiles of histones and corresponding histone chaperone partners are associated with developmental defects and cancer. Here, we discuss the spatiotemporal deposition mechanisms of the Histone H3 variants and their influence on mammalian cell fate during development. We focus on H3 given its profound effect on nucleosome stability and its recently characterized deposition pathways. We propose that differences in deposition of H3 variants are largely dependent on the phase of the cell cycle and cellular potency but are also affected by cellular stress and changes in cell fate. We also discuss the utility of modern technologies in dissecting the spatiotemporal control of H3 variant deposition, and how this could shed light on the mechanisms of cell identity maintenance and lineage commitment. The current knowledge and future studies will help us better understand how organisms employ nucleosome dynamics in health, disease, and aging. Ultimately, these pathways can be manipulated to induce cell fate change in a therapeutic setting depending on the cellular context.
Highlights
The Nucleosome and the Histone H3 FamilyCell fate decisions are central to development, normal homeostasis, and responding to infections, injury, and aging
Histone chaperones are in place to modulate the deposition of histones at the right place and right time and coordinate the action of accompanying chromatin factors, including lineage-specific transcription factors during quiescence, stem cell self-renewal, differentiation, or reprogramming
While the expression of histone variants during the cell cycle and development is well documented, the activity, complex diversity, and interplay of histone chaperones during these processes is poorly understood, especially in the context of cell fate transitions. This is clearly complicated by the multifunctional characteristics of histone chaperones as they play additional roles independent of nucleosome assembly that are in turn linked to chromatin regulation
Summary
Cell fate decisions are central to development, normal homeostasis, and responding to infections, injury, and aging. Work on nucleosome assembly pathways demonstrated a specificity of histone H3 chaperones to assemble nucleosomes in a DNA replication dependent (RD) or independent (RI) manner (Almouzni and Méchali, 1988; Smith and Stillman, 1989; Ray-Gallet et al, 2002) This cell cycle determinant of histone chaperone pathways is further complicated by the specific partnerships of histone chaperones with different variants, parental “old” histones versus newly synthesized histones and the deposition coordinates in the genome (Figure 1). The recent advances in labeling and mapping spatiotemporal distribution of old and new histones, structural mechanisms of histone-chaperone recognition, how they interact directly with DNA templates, and mapping nucleosome positions during different DNA processes have deepened our understanding on how the cell uses nucleosome assembly to maintain or reprogram chromatin organization. While mechanistic studies are largely performed in vitro or in immortal human or mouse cell lines, this knowledge could provide the fundamental mechanisms at play for stem cell maintenance and lineage commitment during development and tissue homeostasis (see sections below)
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