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  • Review Article
  • Published:

Genome-wide approaches to studying chromatin modifications

Nature Reviews Genetics volume 9, pages 179–191 (2008)Cite this article

Key Points

  • Chromatin modifications have been shown to have a profound impact on the regulation of gene expression.

  • Epigenomes consist of the ensemble of all chromatin modifications in any given cell type, including DNA methylation, post-translational histone modifications, nucleosome positioning, histone variants, noncoding RNAs and three-dimensional chromatin architecture.

  • New technologies, which allow for the profiling of chromatin modifications on a genome-wide scale, are providing researchers with comprehensive views of epigenomes.

  • Genome-scale data sets for epigenetic phenomena allow for the use of bioinformatic methods to study epigenetics.

  • Different functional regions of the genome are associated with distinct patterns of histone modifications and these patterns, in turn, can be used to annotate the functional elements in the genome.

Abstract

Over two metres of DNA is packaged into each nucleus in the human body in a manner that still allows for gene regulation. This remarkable feat is accomplished by the wrapping of DNA around histone proteins in repeating units of nucleosomes to form a structure known as chromatin. This chromatin structure is subject to various modifications that have profound influences on gene expression. Recently developed techniques to study chromatin modifications at a genome-wide scale are now allowing researchers to probe the complex components that make up epigenomes. Here we review genome-wide approaches to studying epigenomic structure and the exciting findings that have been obtained using these technologies.

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Figure 1: Genome-wide methods for studying DNA methylation.
Figure 2: Chromatin immunoprecipitation combined with DNA microarrays (ChIP–chip).
Figure 3: Chromatin immunoprecipitation combined with serial analysis of gene expression (ChIP–SAGE).
Figure 4: Chromatin immunoprecipitation combined with high-throughput sequencing techniques (ChIP–Seq).
Figure 5: Characteristics of epigenomes.

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Acknowledgements

We thank members of the Zhao laboratory for helpful discussions. We apologize to those whose work was not included here owing to space limitations. Research in the authors' laboratory is supported by the Intramural Research Program of the US National Institutes of Health, National Heart, Lung and Blood Institute.

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  1. Laboratory of Molecular Immunology, The National Heart, Lung and Blood Institute, National Institutes of Health, Building 10, Room 7B05, 9,000 Rockville Pike, Bethesda, 20892, Maryland, USA

    Dustin E. Schones & Keji Zhao

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Glossary

Chromatin immunoprecipitation

A technique to isolate individual chromatin fragments using an antibody that is specific to a feature of the chromatin fragments (for example, a DNA-binding protein, a particular histone modification, or DNA methylation).

ChIP–chip

The combination of ChIP experiments with DNA microarrays to profile protein targeting or chromatin modifications over large genomic regions.

Serial analysis of gene expression

A sequence-based quantitative technique that is used to determine mRNA levels. cDNA is generated from an mRNA sample, digested with a four-base cutter and ligated to an adaptor containing a class II restriction enzyme that releases a 14 to 21 bp fragment. The short fragments are concatenated together, cloned into a sequencing vector and sequenced.

ChIP–Seq

The combination of ChIP experiments with high-throughput sequencing to quantitatively analyse protein targeting or chromatin modifications across the entire genome.

Tiling microarrays

DNA microarrays with densely spaced or overlapping probes that allow for high-resolution genomic mapping.

Fluorescence in situ hybridization

A technique that involves the fluorescent labelling of single-stranded DNA probes that then target specific regions of chromosomes and allow for the visualization of these regions within the cell.

3C

Chromosome conformation capture. A technique that is used to study the long-distance interactions between genomic regions, which in turn can be used to study the three-dimensional architecture of chromosomes within a cell nucleus.

4C

Either chromosome conformation capture-on-chip or circular chromosome conformation capture. These techniques allow the profiling of many interactions throughout a genome with a specific locus.

5C

Chromosome conformation capture carbon copy. A high-throughput extension of 3C that pairs the 3C technology with DNA microarrays or high-throughput sequencing. This technique allows the profiling of many chromatin interactions in parallel.

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Schones, D., Zhao, K. Genome-wide approaches to studying chromatin modifications. Nat Rev Genet 9, 179–191 (2008). https://doi.org/10.1038/nrg2270

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