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  • Review Article
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New insights into nucleosome and chromatin structure: an ordered state or a disordered affair?

Nature Reviews Molecular Cell Biology volume 13, pages 436–447 (2012)Cite this article

Subjects

Key Points

  • Nucleosomes exist in an assortment of structural states that differ from the various crystal structures.

  • The equilibrium between the nucleosomal states is affected by post-translational modifications (PTMs) of histones, histone variants and DNA sequence.

  • A common interface formed by residues from H2A and H2B is used by several nucleosome-interacting proteins. This 'acidic patch' varies between different histone variants.

  • Several types of chromatin 'secondary structure' may coexist depending on the functional context.

  • An important aspect of chromatin higher-order three-dimensional organization (or 'tertiary structure') is that specific nucleosomes may be distant with respect to their primary structure but may be within interacting distance in the context of tertiary structures, in analogy with protein folding.

  • Small changes in chromatin primary structure yield dramatic effects in its large-scale organization. Numerous and often subtle changes by PTMs, histone variants and DNA sequence can significantly affect nucleosome shape, stability and its protein surface.

Abstract

The compaction of genomic DNA into chromatin has profound implications for the regulation of key processes such as transcription, replication and DNA repair. Nucleosomes, the repeating building blocks of chromatin, vary in the composition of their histone protein components. This is the result of the incorporation of variant histones and post-translational modifications of histone amino acid side chains. The resulting changes in nucleosome structure, stability and dynamics affect the compaction of nucleosomal arrays into higher-order structures. It is becoming clear that chromatin structures are not nearly as uniform and regular as previously assumed. This implies that chromatin structure must also be viewed in the context of specific biological functions.

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Figure 1: Primary, secondary and tertiary structure of chromatin.
Figure 2: Nucleosome structure and the acidic patch: a common interaction interface for many nucleosome-interacting proteins.
Figure 3: The many structural states of the nucleosome.
Figure 4: Two models for chromatin secondary structure.
Figure 5: Nucleosome–nucleosome interactions mediated by histone tails and the nucleosomal surface.
Figure 6: A model for chromatin tertiary structure by interdigitation of nucleosomal arrays.

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Acknowledgements

The authors dedicate this contribution to the late Jonathan Widom in acknowledgement of his pioneering work on chromatin structure and dynamics. Work in the authors' laboratories is supported by the US National Institutes of Health (grant GM088409 to K.L.) and the National Health and Medical Research Council (grants 471422, 1009850 and 1009851 to D.J.T.). K.L. is supported by the Howard Hughes Medical Institute. We thank U. M. Muthurajan for help with figures 2 and 5, and S. Grigoryev for discussion.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, 80523, Colorado, USA

    Karolin Luger & Mekonnen L. Dechassa

  2. Howard Hughes Medical Institute, Fort Collins, 80523, Colorado, USA

    Karolin Luger

  3. The John Curtin School of Medical Research, The Australian National University, P.O. BOX 334, Canberra, 2601, Australian Capital Territory, Australia

    David J. Tremethick

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Glossary

Post-translational modifications

(PTMs). Chemical modifications added post-translationally (and reversibly) to many histone amino acid side chains by highly specific enzymes. PTMs have important functions in the regulation of transcription and DNA repair.

Architectural chromatin proteins

(ACPs). Abundant nuclear proteins that interact with nucleosomes and influence the three-dimensional arrangement of nucleosomal arrays.

Histone chaperones

A diverse group of nuclear proteins that prevent the aggregation of folded histones with DNA during the assembly of nucleosomes. They are also implicated in the transport of histones into the nucleus.

Centromere

The most constricted and compacted region of a chromosome. Spindle fibres attach to the centromere to equally partition newly replicated sister chromatids between daughter cells during cell division.

Sumoylation

A post-translational modification that is involved in various cellular processes, such as nuclear–cytosolic transport, transcriptional regulation, apoptosis, protein stability, response to stress and progression through the cell cycle. It involves the covalent attachment of small ubiquitin-like modifier (SUMO) proteins to other proteins to modify their function.

ATP-dependent chromatin remodelling factors

Large macromolecular complexes that use the energy from ATP hydrolysis to slide, disassemble or otherwise structurally alter nucleosomes.

Fluorescence resonance energy transfer

(FRET; also known as Förster resonance energy transfer). Distance-dependent energy transfer between two chromophores, commonly used to measure conformational changes in a single molecule or to measure interactions between different molecules.

High-speed atomic force microscopy

(High-speed AFM). A high-resolution type of scanning probe microscopy with a demonstrated resolution on the order of fractions of a nanometre. High-speed AFM allows direct visualization of dynamic structural changes and dynamic processes of functioning biological molecules in physiological solutions at high spatiotemporal resolution.

Transient DNA breathing

A transient structural state of the nucleosome characterized by the dissociation of the 10–20 penultimate base pairs of DNA from the histone octamer, leading to 'transient site exposure'.

Open state of the nucleosome

A transient structural state of the nucleosome characterized by the opening of the interface between histone H2A–H2B dimers and (H3–H4)2 tetramers.

Small angle X-ray scattering

(SAXS). A technique in which the elastic scattering of X-rays by a sample is recorded at very low angles. Unlike X-ray crystallography, this technique does not require crystals, and is used to determine the maximum dimensions and overall shape of a macromolecule or a macromolecular complex.

ISWI

The name is derived from its founding member, the Drosophila melanogaster protein imitation switch (ISWI). This family of ATP-dependent chromatin remodellers includes SWI/SNF, ISWI, CHD and INO80 in eukaryotes.

Electron microscopy-assisted nucleosome capture

(EMANIC). A technique whereby nucleosomal arrays or whole cells are subject to controlled formaldehyde crosslinking such that only a few of the nucleosome–nucleosome contacts become covalently linked. Subsequently, the arrays are allowed to disperse in low salt and are imaged by electron microscopy.

Mesoscopic modelling

Pertains to the resolution of the computational approach being the intermediate between the atomic and macroscopic scale. Over a number of years, mesoscopic models of chromatin have been developed that alleviate the prohibitive computational demands of atomistic simulations but incorporate the key features of the chromatin fibre, thereby making it amenable to large-scale simulations.

Ubiquitylation

The covalent attachment of a small protein domain (ubiquitin) to cellular proteins. Monoubiquitylation is a common histone modification; polyubiquitylation (the attachment of multiple molecules of ubiquitin) is usually a marker for intracellular protein transport and degradation. It is found in all cells of higher organisms.

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Luger, K., Dechassa, M. & Tremethick, D. New insights into nucleosome and chromatin structure: an ordered state or a disordered affair?. Nat Rev Mol Cell Biol 13, 436–447 (2012). https://doi.org/10.1038/nrm3382

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