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  • Review Article
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Histone variants meet their match

Nature Reviews Molecular Cell Biology volume 6, pages 139–149 (2005)Cite this article

Key Points

  • Chromatin is organized into specialized domains, some of which contain specialized histones called variant histones. Variant histones have evolved to carry out functions that are distinct from those of the major core histones.

  • Histones are deposited onto DNA by chaperones. Recent studies have shown that some chaperones recruit specific histone variants for deposition. The chaperones HIRA and SWR1 specifically recruit and exchange the histone variants H3.3 and H2AZ, respectively, whereas the chromatin assembly factor-1 (CAF1) mediates the deposition of the H3.1 major core histone in a process that is coupled to DNA replication.

  • The implications of two modes of deposition of the histones H3 and H4 (that is, tetramers versus dimers) are discussed, as they are important for the transmission of epigenetic information from the mother to the daughter cells.

  • The functions and possible modes of deposition of other variant histones such as CENPA, H2AX and others are also discussed.

  • Both H3.3 and H2AZ have been suggested to function in activated transcription on the basis of their localization to euchromatic loci. Models are proposed whereby histone exchangers coordinate with FACT — a chaperone that has a crucial role in facilitating transcription elongation on chromatin — to allow the incorporation of histone variants during the process of transcription.

  • A model is also presented that addresses CAF1-mediated deposition of histone H3 that is methylated at Lys9, through CAF1 interaction with the histone methyltransferase SUV39H1, which results in the formation of repressive chromatin.

Abstract

A fascinating aspect of how chromatin structure impacts on gene expression and cellular identity is the transmission of information from mother to daughter cells, independently of the primary DNA sequence. This epigenetic information seems to be contained within the covalent modifications of histone polypeptides and the distinctive characteristics of variant histone subspecies. There are specific deposition pathways for some histone variants, which provide invaluable mechanistic insights into processes whereby the major histones are exchanged for their more specialized counterparts.

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Figure 1: Canonical core histones and their variants.
Figure 2: Synergism between SWR1, HIRA and FACT.
Figure 3: Mechanism of repression by histone-exchange complexes and histone methyltransferases.

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Acknowledgements

We thank Ken Marians, Jerry Hurwitz, Steven Henikoff, Yoshihiro Nakatani and Geneviève Almouzni for helpful discussions. We would also like to thank Lynne Vales for critical reading of the manuscript and members of the Reinberg laboratory for discussions. We apologize to colleagues whose work we have not cited owing to space limitations. This work was supported by grants from the National Institutes of Health and the Howard Hughes Medical Institute to D.R.

Author information

Authors and Affiliations

  1. Division of Nucleic Acids Enzymology, Department of Biochemistry, Howard Hughes Medical Institute, Robert Wood Johnson Medical School, Piscataway, 08854, New Jersey, USA

    Kavitha Sarma & Danny Reinberg

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  1. Kavitha Sarma
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Correspondence to Danny Reinberg.

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DATABASES

Swiss-Prot

Bdf1

CAF1

CENPA

Cse4

H2ABBD

H2AX

H2AZ

H3.1

H3.2

H3.3

HIRA

macroH2A

PCNA

Swr1

Spt6

FURTHER INFORMATION

Kavitha Sarma's web page

Danny Reinberg's laboratory

Glossary

ORPHAN GENE

A protein-coding region that bears little or no homology to genes in distant species.

HISTONE LYSINE METHYLTRANSFERASE

An enzyme that catalyses the transfer of methyl groups onto the ε-amino residue of lysines in histones.

ALPHA SATELLITE REPEAT

Large highly repetitive stretches of (A+T)-rich DNA sequences in the human genome that are usually untranscribed.

HISTONE CHAPERONE

A protein that escorts histones to DNA for deposition.

CHROMATIN-REMODELLING FACTOR

A protein that alters the dynamic organization of nucleosomes to help in the activation or repression of gene expression.

HISTONE ACETYLTRANSFERASE

An enzyme that catalyses the addition of an acetyl group to specific lysine residues in histones.

MACRONUCLEUS

The larger of the two nuclei in the unicellular ciliate Tetrahymena thermophila. This is the somatic nucleus and is transcriptionally active.

MICRONUCLEUS

The smaller 'germline' nucleus in Tetrahymena thermophila, which is transcriptionally silent.

CONJUGATION

A process of sexual reproduction that occurs in some unicellular organisms and that involves the exchange of genetic material between two cells through a so-called sex pilus.

MATING-TYPE LOCUS

The genomic region in yeast that determines the mating type or 'sex' of the haploid yeast cell.

BROMODOMAIN

An evolutionarily conserved domain that has been shown to bind to acetylated residues.

CHROMATIN IMMUNOPRECIPITATION

(ChIP). A technique by which direct or indirect protein–DNA interactions in chromatin can be studied using antibodies against specific chromosomal proteins.

X INACTIVATION

The process whereby one of the two copies of the X chromosome in female mammals is silenced to compensate for the presence of a single copy in males.

LEUCINE-ZIPPER MOTIF

A leucine-rich protein domain that mediates interactions with other proteins with a similar domain.

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Sarma, K., Reinberg, D. Histone variants meet their match. Nat Rev Mol Cell Biol 6, 139–149 (2005). https://doi.org/10.1038/nrm1567

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