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Multifunctional histone variants in genome function

Nature Reviews Genetics (2024)Cite this article

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Abstract

Histones are integral components of eukaryotic chromatin that have a pivotal role in the organization and function of the genome. The dynamic regulation of chromatin involves the incorporation of histone variants, which can dramatically alter its structural and functional properties. Contrary to an earlier view that limited individual histone variants to specific genomic functions, new insights have revealed that histone variants exert multifaceted roles involving all aspects of genome function, from governing patterns of gene expression at precise genomic loci to participating in genome replication, repair and maintenance. This conceptual change has led to a new understanding of the intricate interplay between chromatin and DNA-dependent processes and how this connection translates into normal and abnormal cellular functions.

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Fig. 1: Histone variants throughout the cell cycle.
Fig. 2: Primary structure of histone variants and their influence on nucleosome structure.
Fig. 3: The role of histone variants in establishing different transcriptional chromatin states.
Fig. 4: The role of histone variants in double-strand DNA break repair.
Fig. 5: The organization of histone variant-containing chromatin in centromeres and pericentric heterochromatin.
Fig. 6: Normal and abnormal roles of histone variants and their chaperone complexes.

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Acknowledgements

The authors thank T. Cesare for his critical feedback. They thank the researchers who have made valuable contributions to the dynamic and evolving field of histone variants. This work was supported by the Australian Research Council, DP230102695 (L.H.W.), DP230101039 (D.J.T.); and the National Health and Medical Research Council, APP2012764 (L.H.W.), APP1182759 (D.J.T.).

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  1. Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia

    Lee H. Wong

  2. The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capial Territory, Australia

    David J. Tremethick

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Glossary

ATP-dependent remodelling complexes

These complexes use the energy derived from ATP to remodel and disrupt the structure of chromatin and thereby regulate access to DNA to gene regulatory proteins and histone-modifying enzymes.

Bivalent nucleosome

A nucleosome that is characterized by the simultaneous presence of two distinct histone modifications that have opposing roles in gene regulation: H3K4me3 (active) and H3K27me3 (inactive).

Cohesin-mediated loop extrusion

The cohesin complex extrudes or ‘loops out’ a segment of chromatin as it moves along DNA. The generation of chromatin loops brings together regions of DNA that are far apart.

Inner kinetochore proteins

A group of proteins that form a structure on the centromere that is required for the attachment spindles. This is crucial for the proper segregation of chromosomes during cell division.

Intracisternal A-particle endogenous retroviral elements

Retrotransposons that are significant components of the mouse genome and contribute to both genome evolution and genomic instability and disease.

Nuclear lamins

Structural proteins found at the nuclear periphery and the nucleoplasm, which have a major influence on genome organization, nuclear morphology and gene regulation.

PARylation

A post-translational modification (poly(ADP-ribosyl)ation) of proteins whereby ADP-ribose polymers are attached to target proteins mediated by poly(ADP-ribose) polymerases (PARPs).

Phase separation

A physical process in which proteins with certain properties separate into distinct liquid-like or even solid-like phases believed to be important for the formation of functional domains within a cell.

Pioneer transcription factors

A special class of transcription factors that can bind to nucleosomal DNA and initiate the process of chromatin opening, thereby enabling the recruitment of other chromatin regulators required for gene activation.

R-loops

Three-stranded nucleic acid structures that form when an RNA molecule displaces one of the DNA strands in a DNA duplex, resulting in an RNA–DNA hybrid and a displaced single-stranded DNA region.

Topologically associating domain

(TAD). Self-interacting region of the genome in which DNA sequences within a TAD tend to physically interact with each other more frequently than with sequences outside the TAD, which brings together regulatory elements.

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Wong, L.H., Tremethick, D.J. Multifunctional histone variants in genome function. Nat Rev Genet (2024). https://doi.org/10.1038/s41576-024-00759-1

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