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The roles of histone variants in fine-tuning chromatin organization and function

Nature Reviews Molecular Cell Biology volume 21, pages 522–541 (2020)Cite this article

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Abstract

Histones serve to both package and organize DNA within the nucleus. In addition to histone post-translational modification and chromatin remodelling complexes, histone variants contribute to the complexity of epigenetic regulation of the genome. Histone variants are characterized by a distinct protein sequence and a selection of designated chaperone systems and chromatin remodelling complexes that regulate their localization in the genome. In addition, histone variants can be enriched with specific post-translational modifications, which in turn can provide a scaffold for recruitment of variant-specific interacting proteins to chromatin. Thus, through these properties, histone variants have the capacity to endow specific regions of chromatin with unique character and function in a regulated manner. In this Review, we provide an overview of recent advances in our understanding of the contribution of histone variants to chromatin function in mammalian systems. First, we discuss new molecular insights into chaperone-mediated histone variant deposition. Next, we discuss mechanisms by which histone variants influence chromatin properties such as nucleosome stability and the local chromatin environment both through histone variant sequence-specific effects and through their role in recruiting different chromatin-associated complexes. Finally, we focus on histone variant function in the context of both embryonic development and human disease, specifically developmental syndromes and cancer.

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Fig. 1: Core histones, their variants and associated chaperone/remodeller machineries.
Fig. 2: Variant-containing nucleosomes influence nucleosome stability and chromatin properties.
Fig. 3: Variant-containing nucleosomes influence chromatin through various mechanisms.
Fig. 4: Expression of histone variants during embryonic development.
Fig. 5: ATRX-dependent mechanisms in physiology, cancer and human genetic disease.

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Acknowledgements

The authors thank E. Duncan and the reviewers for critical comments on this manuscript. L.A.B. is a Virginia Murchison Linthicum Scholar in Medical Research (University of Texas Southwester Medical Center Endowed Scholars Program in Medical Science) and a Peterson Investigator of the Neuroendocrine Research Foundation. This work was supported in part by grants form the Cancer Prevention and Research Institute of Texas (RR140042), the Welch Foundation (I-2025), the US Department of Defense (KCRP KC170230) and the NIH (R35 GM124958) to L.A.B., the American-Italian Cancer Foundation (S.M.) and the Green Center for Reproductive Biology Sciences.

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  1. Green Center for Reproductive Biology Sciences, Department of Obstetrics and Gynecology, Children’s Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Sara Martire & Laura A. Banaszynski

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  1. Sara Martire
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Glossary

Endogenous retroviral elements

Subset of transposable elements (up to 8% of the total genome) with long terminal repeats, which can act as transcriptional elements.

Imprinted regions

Regions of the genome that harbour genes that are expressed in a parental origin-specific manner.

Micrococcal nuclease

Non-specific DNA and RNA endo–exonuclease that preferentially digests non-nucleosomal DNA.

G-quadruplex

Guanine-rich DNA sequence that can fold into four-stranded, non-canonical secondary structures and is involved in genome functions such as replication and genome stability.

Centromere-associated network (CCAN) proteins

Subcomplex in the kinetochore that binds centromeric chromatin and functions as a foundation for kinetochore formation.

Poly(ADP-ribose)

Reversible post-translational modification resulting in the covalent attachment of polymers of ADP-ribose units on target proteins.

Polycomb repressive complex

Repressor family of protein complexes important for developmental gene regulation and embryo patterning through enzymatic activity on histone proteins.

Facultative heterochromatin

Type of heterochromatin that has the ability to become transcriptionally active again (that is, the inactive X chromosome in mammals), typically marked by Polycomb group protein activity.

Liquid–liquid phase separation

Physical process by which cells create non-membrane-bound compartments (biomolecular condensates) that have been implicated in various cellular processes from signalling to gene regulation.

Heterochromatin protein 1

Family of chromodomain proteins that bind to H3K9me3 and are required for the formation of transcriptionally inactive heterochromatin.

+1 nucleosome

The first (+1) nucleosome positioned after a promoter-associated nucleosome-free region.

Alternative lengthening of telomeres (ALT) pathway

Telomerase-independent mechanism (homologous recombination-mediated DNA replication based) by which a number of human tumours maintain their telomeres.

Mitotic bookmark

Binding by transcription and chromatin regulators at regulatory elements during mitosis to convey gene regulatory information to daughter cells.

Protamines

Small proteins that replace histones during spermatogenesis, allowing denser packaging of DNA in the sperm than would be achieved with histones.

Pronucleus

Cell nucleus characterized by a haploid set of chromosomes resulting from meiosis (female pronucleus) or just before fertilization (male pronucleus).

Zygotic genome activation

Also known as maternal-to-zygotic transition, refers to the process that enables zygotic gene products to replace the maternal supply that initiated development.

Trophoblast

Part of the outer trophectoderm layer. These cells contribute to extraembryonic tissues such as fetal placenta and to processes of early development.

X chromosome inactivation

Transcriptional silencing of a random X chromosome in female mammalian cells that equalizes the dosage of gene products from the X chromosome between XX females and XY males.

Epithelial–mesenchymal transition

Process that occurs during both development and cancer progression in which epithelial cells lose their adhesive properties to become invasive mesenchymal cells.

Homologous recombination-dependent telomere sister chromatid exchange

Telomere extension events with crossover formation between sister chromatids, which are used as a template to repair homology-directed damaged telomeres.

α-Thalassaemia X-linked mental retardation syndrome

Rare X-linked recessive syndrome caused by mutations in the ATRX gene, characterized by intellectual disability and reduced production of haemoglobin.

Floating-Harbor syndrome

(FHS). Rare autosomal dominant disease caused by mutations in the SRCAP gene, characterized by a distinctive facial appearance, various skeletal malformations, delayed bone age and expressive and receptive language delays.

Neural crest

Transient developmental structure unique to vertebrates that gives rise to diverse lineages, including melanocytes, craniofacial cartilage and bone, and most of the peripheral nervous system.

Promyelocytic leukaemia nuclear bodies

Nuclear matrix-associated structures with characteristics of biomolecular condensates that contain promyelocytic leukaemia proteins, which are required for the assembly of a number of nuclear structures.

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Martire, S., Banaszynski, L.A. The roles of histone variants in fine-tuning chromatin organization and function. Nat Rev Mol Cell Biol 21, 522–541 (2020). https://doi.org/10.1038/s41580-020-0262-8

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