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  • Review Article
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ChIP–seq: advantages and challenges of a maturing technology

Key Points

  • Chromatin immunoprecipitation followed by sequencing (ChIP–seq) can be used to map DNA-binding proteins and histone modifications in a genome-wide manner at base-pair resolution.

  • ChIP–seq offers superior data quality to chromatin immunoprecipitation followed by microarray (ChIP–chip), and its advantages include higher resolution, less noise, higher genome coverage and wider dynamic range.

  • To eliminate bias in fragmentation and sequencing, a control sample (generally input DNA) should also be sequenced. Other issues to consider in experimental design include the quality of the antibodies and the depth of sequencing.

  • Genome alignment and the identification of enriched regions present challenges for data analysis, and there are several strategies available.

  • Owing to increased genome coverage, a substantial fraction of the repetitive regions in the genome can now be examined.

  • Increased sensitivity and specificity in the mapping of transcription factor binding sites has facilitated motif discovery and target identification.

  • Detailed profiling of histone modifications and nucleosome positions enables greater understanding of epigenetic mechanisms in development and differentiation.

  • As the cost of sequencing continues to decrease, ChIP–seq will be the method of choice over array-based approaches in nearly all cases.

Abstract

Chromatin immunoprecipitation followed by sequencing (ChIP–seq) is a technique for genome-wide profiling of DNA-binding proteins, histone modifications or nucleosomes. Owing to the tremendous progress in next-generation sequencing technology, ChIP–seq offers higher resolution, less noise and greater coverage than its array-based predecessor ChIP–chip. With the decreasing cost of sequencing, ChIP–seq has become an indispensable tool for studying gene regulation and epigenetic mechanisms. In this Review, I describe the benefits and challenges in harnessing this technique with an emphasis on issues related to experimental design and data analysis. ChIP–seq experiments generate large quantities of data, and effective computational analysis will be crucial for uncovering biological mechanisms.

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Figure 1: Overview of a ChIP–seq experiment.
Figure 2: ChIP profiles.
Figure 3: Depth of sequencing.
Figure 4: Overview of ChIP–seq analysis.
Figure 5: Strand-specific profiles at enriched sites.

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Acknowledgements

I thank P. Kharchenko, M. Tolstorukov, A. Alekseyenko and other members of the Park and the Kuroda laboratories for their insights. I gratefully acknowledge support from the National Institutes of Health grants R01GM082798, U01HG004258 and RL1DE019021.

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Glossary

Nucleosome

The basic structural subunit of chromatin. A nucleosome consists of approximately 147 base pairs of DNA and an octamer of histone proteins.

Epigenome

The chromatin states that are found along the genome, defined for a given time point and cell type. Thus, for a given genome there may be hundreds or thousands of epigenomes, depending on the stability of the chromatin states.

DNase I hypersensitive site

A chromosomal region that is highly accessible to cleavage by DNase I. Such sites are associated with open chromatin conformations and transcriptional activity.

Bivalent domain

A region of chromatin marked by a histone modification associated with active transcription (histone H3 lysine 4 trimethylation) and a modification associated with repression (histone H3 lysine 27 trimethylation). It is postulated to mark genes that are silent but poised for transcription.

Imprinting

The differential expression of genes depending on whether they were inherited maternally or paternally.

Heterochromatin

A region of highly compact chromatin. Constitutive heterochromatin is largely composed of repetitive DNA.

Microsatellite

A class of repetitive DNA that is made up of repeats that are 2–8 nucleotides in length.

RNA interference

The process by which the introduction or expression within cells of single- or double-stranded RNA leads to the degradation of mRNA and therefore to gene suppression.

Poisson model

A probability distribution that is often used to model the number of random events in a fixed interval. Given an average number of events in the interval, the probability of a given number of occurrences can be calculated.

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Park, P. ChIP–seq: advantages and challenges of a maturing technology. Nat Rev Genet 10, 669–680 (2009). https://doi.org/10.1038/nrg2641

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