Review Article | Published:

Histone exchange, chromatin structure and the regulation of transcription

Nature Reviews Molecular Cell Biology volume 16, pages 178189 (2015) | Download Citation

Abstract

The packaging of DNA into strings of nucleosomes is one of the features that allows eukaryotic cells to tightly regulate gene expression. The ordered disassembly of nucleosomes permits RNA polymerase II (Pol II) to access the DNA, whereas nucleosomal reassembly impedes access, thus preventing transcription and mRNA synthesis. Chromatin modifications, chromatin remodellers, histone chaperones and histone variants regulate nucleosomal dynamics during transcription. Disregulation of nucleosome dynamics results in aberrant transcription initiation, producing non-coding RNAs. Ongoing research is elucidating the molecular mechanisms that regulate chromatin structure during transcription by preventing histone exchange, thereby limiting non-coding RNA expression.

Key points

  • Histone exchange involves the partial or complete exchange of nucleosomes for newer or altered components. This process occurs sequentially through the removal and the replacement of the H2A–H2B dimers followed by the H3–H4 tetramer.

  • Several factors that affect the stability of the nucleosome influence the process of histone exchange. These include chromatin modifiers, chromatin remodellers and histone chaperones.

  • Destabilization of the nucleosome allows histone exchange to proceed, often resulting in the replacement of canonical histones with variants that carry out specialized cellular functions.

  • Histone exchange features prominently during the process of transcription initiation and elongation. A combination of variant exchange and turnover of histone subunits drives RNA polymerase II (Pol II)-mediated transcription.

  • Resetting of chromatin is a crucial process used by the cell to reassemble the nucleosomes that are lost during the transcription process. The co-transcriptional histone H3 lysine 36 methylation mark uses a multipronged approach to prevent histone exchange over coding regions.

  • Limiting unobstructed histone exchange over coding regions of genes is necessary to prevent aberrant initiation of transcription. Given the importance of non-coding RNA in the development of diseases, understanding how they are produced has immense value.

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Acknowledgements

The authors thank K. Natarajan for critical reading of this manuscript and apologize to several colleagues whose work could not be cited here because of space restrictions. This work was supported in part by the US National Institutes of Health (NIH) grant NIH R01GM047867 to J.L.W. and the Stowers Institute for Medical Research.

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Affiliations

  1. Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA.

    • Swaminathan Venkatesh
    •  & Jerry L. Workman

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Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Swaminathan Venkatesh or Jerry L. Workman.

Glossary

Histone variants

Histone protein isoforms transcribed from distinct genomic loci that can replace the typical histone proteins in a defined manner in order to achieve specialized functions.

Linker histone H1

A component of the nucleosome that is necessary to lock the DNA wrapped around the histone core at the dyad axis and to contribute to the higher-order structure of chromatin. It does not contain the histone-fold domain and is not a part of the globular core of the nucleosome.

Chromosomal domain segregation

The separation of chromatin, on the basis of the packing density, into euchromatin (less dense) and heterochromatin (more dense) domains, which are separated by distinct chromatin structures that often involve the H2A.Z histone variant.

Ubiquitylation

A post-translational modification on histones that adds a single ubiquitin protein molecule to lysine residues, resulting in transcriptional regulation. This is different from the addition of a chain of ubiquitin molecules, which usually signals for degradation.

Sumoylation

A post-translational modification similar to ubiquitylation, in which a small ubiquitin-like modifier (SUMO) protein is added to lysine residues to regulate transcription. In contrast to ubiquitylation, sumoylation is not involved in protein degradation.

Open chromatin

A qualitative term applied to the fluid state of chromatin that allows easy access to the DNA; it is usually associated with active post-translational modification marks.

Closed chromatin

A qualitative term applied to the static state of chromatin that prevents access to the DNA because of the addition of repressive post-translational modification marks and the binding of factors that pack nucleosomes into a compact structure.

Readers

Dedicated protein factors that have the ability, through specialized domains, to recognize either specific post-translational marks on histones or a combination of marks and histone variants to direct a particular transcriptional outcome.

Writers

Enzymes that add post-translational modifications on histones. Each is specific for a particular class of post-translational modification (for example, kinases for phosphorylation and methyltransferases for methylation).

Erasers

Enzymes that remove specific post-translational modification marks from histone substrates and that belong to various classes (for example, phosphatases for dephosphosphorylation and demethylases for demethylation).

DNA translocase

An enzyme that catalyses the ATP-dependent breakage of histone–DNA contacts and the subsequent pushing of the dislocated DNA segment, which results in its movement around a central anchored nucleosome.

SNF2 family

A large family of DNA-dependent ATPases, which are helicase-like proteins involved in chromatin remodelling. The family was identified on the basis of protein sequence homology to the ATPase domain of yeast Snf2.

Histone acetyltransferase

An enzyme that catalyses the addition of an acetyl moiety from the donor acetyl coenzyme A to lysine residues on histones.

Histone sinks

Proteins (often histone chaperones) that accept histone subunits removed from nucleosomes, which prevent their nonspecific association with DNA.

Histone methyltransferase

An enzyme that catalyses the addition of up to three methyl moieties from the donor S-adenosyl methionine to lysine residues on histone proteins.

PWWP domain

A 135 amino acid protein domain characterized by a central proline-tryptophan-tryptophan-proline core, that recognizes methylated lysines (particularly H3 K36) as a part of several eukaryotic proteins involved in chromatin regulation, DNA repair and transcriptional regulation.

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DOI

https://doi.org/10.1038/nrm3941

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