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Variants of core histones and their roles in cell fate decisions, development and cancer

Nature Reviews Molecular Cell Biology volume 18, pages 299–314 (2017)Cite this article

Subjects

Key Points

  • Histone variants have evolved to endow chromatin with special properties in a locus-specific manner, and they differ from replication-coupled ('canonical') histones in terms of their gene composition, RNA processing, expression and deposition timing, and protein structure.

  • Specific chaperones and chromatin remodellers regulate the chromatin incorporation and removal of histone variants, and they can act in a locus-specific manner.

  • Histone variants are dynamically expressed during early embryonic development and have specialized functions during lineage commitment and during somatic cell reprogramming.

  • In cancer, histone variants and their regulators are frequently deregulated at the level of transcription and in some cases by mutations.

  • The deregulation of histone variants contributes to cancer through multiple mechanisms, including altered transcription, increased epigenetic plasticity and the induction of genomic instability.

  • As an example, lysine residues 27 and 36 of H3.3 (as well as those of the replication-coupled H3.1) can be modified by methylation and are frequently mutated in childhood cancers. These are gain-of-function mutations. The mutant proteins act as inhibitors of specific histone methyltransferases and probably drive cancer by perturbing epigenetic regulation in a restricted developmental time window.

Abstract

Histone variants endow chromatin with unique properties and show a specific genomic distribution that is regulated by specific deposition and removal machineries. These variants — in particular, H2A.Z, macroH2A and H3.3 — have important roles in early embryonic development, and they regulate the lineage commitment of stem cells, as well as the converse process of somatic cell reprogramming to pluripotency. Recent progress has also shed light on how mutations, transcriptional deregulation and changes in the deposition machineries of histone variants affect the process of tumorigenesis. These alterations promote or even drive cancer development through mechanisms that involve changes in epigenetic plasticity, genomic stability and senescence, and by activating and sustaining cancer-promoting gene expression programmes.

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Figure 1: Comparing replication-coupled and variant human core histones.
Figure 2: The roles of histone chaperones and remodellers, and the impact of histone variants on chromatin.
Figure 3: The dynamic expression and function of histone variants during embryonic development and cell fate transitions, and the contribution of variants to the histone pool.
Figure 4: Deregulation of the histone variant network in cancer.

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Acknowledgements

The authors thank E. Bernstein for critical reading of the manuscript and for her insightful suggestions. This work was supported by the Ministry of Economy and Competitiveness (MINECO; grants BFU2015-66559-P and PIE16-00011 to M.B.); the Deutsche Jose Carreras Leukämie Stiftung (grant DJCLS R 14/16 to M.B.); AFM Téléthon (grant AFM 18738 to M.B.); Fundació Internacional Josep Carreras (M.B.); Foundation 'Obra Social la Caixa' (M.B.); Agency for Management of University and Research Grants (AGAUR; grant 2014-SGR-35 to M.B.), the European Commission (grant H2020-MSCA-ITN-2015-675610 to M.B.); the Deutsche Forschungsgemeinschaft (DFG; CRC1064, project A10; grant HA5437/6-1 to S.B.H.); Weigand'sche Stiftung (S.B.H.); and the Center for Integrated Protein Science Munich, Germany (S.B.H.).

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  1. Sandra B. Hake

    Present address: Present address: Institute for Genetics, Justus Liebig University Giessen, 35392 Giessen, Germany.,

Authors and Affiliations

  1. Josep Carreras Leukaemia Research Institute, Campus Institut Català d'Oncologia – Germans Trias i Pujol, Campus Can Ruti, Badalona, 08916, Spain

    Marcus Buschbeck

  2. Program for Predictive and Personalized Medicine of Cancer, Germans Trias i Pujol Research Institute, Badalona, 08916, Spain

    Marcus Buschbeck

  3. Center for Integrated Protein Science Munich and Department of Molecular Biology, BioMedical Center, Ludwig-Maximilians University Munich, 82152, Planegg-Martinsried, Germany

    Sandra B. Hake

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Glossary

Urochordates

Also called tunicates. Small marine invertebrates that exhibit a simplified chordate body plan and are within the chordate phylum, which includes the closest relatives of vertebrates.

Pseudogenes

Genes and gene copies that have lost their protein-coding function.

Histone chaperones

Histone-binding proteins that facilitate histone-dependent processes, including histone deposition on and removal from chromatin.

Chromatin remodellers

Frequently multimeric complexes that use ATP to catalyse changes in chromatin structure, including the exchange of histones.

Retrotransposons

Ubiquitous genetic elements that are able to amplify themselves.

Centromere

A chromosome region that mediates attachment to the mitotic spindle during mitosis.

Inner cell mass

Pluripotent cells of the blastocyst.

Kinetochore

A multiprotein complex assembled on the centromere that mediates the interaction with the microtubules of the spindle.

Totipotent cells

Cells that can give rise to all embryonic and extra-embryonic tissues.

Epithelial–mesenchymal transition

(EMT). The switch of cells from an epithelial to a mesenchymal morphology.

G2–M checkpoint

A control mechanism that allows cell cycle progression only in the absence of DNA damage.

Homologous recombination

The exchange of DNA sequences between different chromosome copies.

Non-homologous end joining

(NHEJ). A DNA repair pathway that ligates DNA break ends independently of their sequence.

Neocentromeres

New centromeres that form on chromosome arms.

Pericentromeric heterochromatin

Heterochromatin regions that flank the centromere.

Alternative lengthening of telomeres pathway

(ALT pathway). A telomerase-independent mechanism of telomere maintenance in proliferating cells.

G quadruplexes

Stable non-helical tertiary structures formed from guanine-rich nucleic acid sequences.

rDNA clusters

Arrays of repeated sequences that encode the RNA components of ribosomes.

Paracrine senescence

Irreversible cell cycle arrest induced by paracrine factors that are secreted by other senescent cells.

Long interspersed element 1 repeat elements

(LINE1 repeat elements). A large family of mammalian retrotransposons.

Oncogene-induced senescence

Irreversible cell cycle arrest induced by acute oncogene overexpression.

Promyelocytic leukaemia bodies

(PML bodies). Nuclear bodies formed by the protein PML and multiple other proteins that interact with PML.

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Buschbeck, M., Hake, S. Variants of core histones and their roles in cell fate decisions, development and cancer. Nat Rev Mol Cell Biol 18, 299–314 (2017). https://doi.org/10.1038/nrm.2016.166

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