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Nucleosome destabilization in the epigenetic regulation of gene expression

Nature Reviews Genetics volume 9, pages 15–26 (2008)Cite this article

Key Points

  • Chromatin has been implicated in the epigenetic inheritance of gene activity; however, the mechanism whereby an active or silent state of a gene is inherited is poorly understood.

  • The stability of nucleosomes is affected by the action of ATP-dependent nucleosome remodellers that can move nucleosomes from energetically favourable positions to inherently less stable positions, and by the action of the Asf1 histone escort and disassembly protein.

  • Bulk chromatin that is deposited during replication can be dynamically replaced during the remainder of the cell cycle by a replication-independent nucleosome-assembly pathway that deposits the H3.3 histone variant, which is enriched for 'active' post-translational modifications.

  • Promoters and regulatory elements that have been implicated in epigenetic inheritance are sites of enhanced histone turnover, which maintains the accessibility of DNA for binding by sequence-specific DNA-binding proteins.

  • The modification of histone tails and the binding of chromatin-associated proteins can modulate the accessibility of regulatory DNA by altering nucleosome stability.

  • The variant composition of a nucleosome can affect its inherent stability, potentially making it more easily evicted at sites of gene regulatory processes.

  • It is proposed that active chromatin propagates itself by the continual action of protein complexes that evict nucleosomes, allowing transient access of DNA-binding proteins to their binding sites.

Abstract

Assembly, mobilization and disassembly of nucleosomes can influence the regulation of gene expression and other processes that act on eukaryotic DNA. Distinct nucleosome-assembly pathways deposit dimeric subunits behind the replication fork or at sites of active processes that mobilize pre-existing nucleosomes. Replication-coupled nucleosome assembly appears to be the default process that maintains silent chromatin, counteracted by active processes that destabilize nucleosomes. Nucleosome stability is regulated by the combined effects of nucleosome-positioning sequences, histone chaperones, ATP-dependent nucleosome remodellers, post-translational modifications and histone variants. Recent studies suggest that histone turnover helps to maintain continuous access to sequence-specific DNA-binding proteins that regulate epigenetic inheritance, providing a dynamic alternative to histone-marking models for the propagation of active chromatin.

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Figure 1: Asf1 is involved in both nucleosome assembly and disassembly.
Figure 2: Histone H3.3 marks active chromatin.
Figure 3: Histone replacement at regulatory elements.
Figure 4: Model for constitutive accessibility at a cis-regulatory site mediated by histone turnover.
Figure 5: Modulation of nucleosome stability.

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Acknowledgements

I thank K. Ahmad, Y. Mito, T. Furuyama and other past and present members of my laboratory for the many stimulating discussions and ideas that have contributed to this synthesis.

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  1. Basic Sciences Division, Howard Hughes Medical Institute, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, 98109, Washington, USA

    Steven Henikoff

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Glossary

Position-effect variegation

The variable, heritable silencing of genes by their juxtaposition to heterochromatin, or by movement of a gene into a different nuclear domain or chromosomal context.

Satellite DNA

Various classes of highly repetitive DNA that are tandemly repeated and are most often associated with centromeric or pericentromeric regions of the genome; -satellite DNA is the primate centromere-specific satellite in which the monomeric unit is 171 bp.

Boundary element

A genetic element that separates independent cis-acting regulatory domains, or separates active from silent chromatin, preventing them from 'spreading' into one another.

Insulator

A segment of DNA that prevents silencing of a reporter gene by adjacent heterochromatin. Some insulators have been demonstrated to be boundary elements in their native context.

CTCF

A highly conserved DNA-binding protein with 11 zinc fingers that binds to insulators and boundaries in mammalian genomes.

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Henikoff, S. Nucleosome destabilization in the epigenetic regulation of gene expression. Nat Rev Genet 9, 15–26 (2008). https://doi.org/10.1038/nrg2206

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  • DOI: https://doi.org/10.1038/nrg2206

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