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Charting histone modifications and the functional organization of mammalian genomes

Key Points

  • Large-scale mapping of chromatin features has emerged as a powerful tool to understand the global landscape of genome regulation. In particular, chromatin immunoprecipitation followed by sequencing (ChIP–seq) has generated vast amounts of data on the genome-wide distribution of histone modifications across various cell types.

  • Eukaryotic chromatin structure can be viewed as superimposed organizational layers, from DNA sequence, to nucleosomes, to histone modifications and variants and, finally, to higher-order structures.

  • Histone modifications demarcate functional elements, including promoters, gene bodies, enhancers and boundary elements, in the large expanse of the mammalian genome.

  • Promoters are subject to distinct chromatin patterns and regulation according to their CpG content. Namely, high CpG content promoters assume an active conformation by default and low CpG content promoters are inactive by default.

  • Histone modifications may fine-tune the activities of promoters, gene bodies and enhancers, and the stability of repressive domains.

  • Emerging evidence suggests that there are global correspondences between histone modification patterns, replication timing and higher-order nuclear structures.


A succession of technological advances over the past decade have enabled researchers to chart maps of histone modifications and related chromatin structures with increasing accuracy, comprehensiveness and throughput. The resulting data sets highlight the interplay between chromatin and genome function, dynamic variations in chromatin structure across cellular conditions, and emerging roles for large-scale domains and higher-ordered chromatin organization. Here we review a selection of recent studies that have probed histone modifications and successive layers of chromatin structure in mammalian genomes, the patterns that have been identified and future directions for research.

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Figure 1: Layers of chromatin organization in the mammalian cell nucleus.
Figure 2: Histone modifications demarcate functional elements in mammalian genomes.
Figure 3: Chromatin patterns and regulation by promoter class.
Figure 4: 'Dashboard' of histone modifications for fine-tuning genomic elements.
Figure 5: Histone modification signatures associated with features in the mammalian cell nucleus.


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We thank E. Mendenhall, M. Ku, R. Koche and E. Rheinbay for critical reading of the manuscript. We also thank members of the Bernstein laboratory for insightful discussions. V.W.Z. was supported by a National Defense Science and Engineering Graduate Fellowship and a National Science Foundation Graduate Research Fellowship. A.G. was supported by an EMBO long-term postdoctoral fellowship. B.E.B. is an Early Career Scientist of the Howard Hughes Medical Institute. Research in the Bernstein laboratory is supported by funds from the Burroughs Wellcome Fund, Howard Hughes Medical Institute and the National Institutes of Health.

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Correspondence to Bradley E. Bernstein.

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Nature Reviews Genetics article series on Applications of next-generation sequencing


CpG island

A genomic region enriched for CpG dinucleotides that often occurs near constitutively active promoters. Mammalian genomes are otherwise depleted of CpGs owing to the preferential deamination of methylated cytosines.


Chromatin immunoprecipitation followed by sequencing. A method for mapping the distribution of histone modifications and chromatin-associated proteins genome wide that relies on immunoprecipitation with antibodies to modified histones or other chromatin proteins. The enriched DNA is sequenced to create genome-wide profiles.

DNase I-seq

DNase I digestion followed by sequencing. A method that distinguishes open chromatin regions based on their hypersensitivity to DNase I digestion. Sequencing these genomic fragments can generate genome-wide maps of chromatin accessibility.


Formaldehyde Assisted Isolation of Regulatory Elements followed by sequencing exploits the solubility of open chromatin in the aqueous phase during phenol-chloroform extraction to generate genome-wide maps of soluble chromatin.


Sonication followed by sequencing. A technique that relies on the increased sonication efficiency of open crosslinked chromatin to identify regions of increased accessibility genome-wide.


Micrococcal nuclease digestion followed by sequencing. A method that distinguishes nucleosome positioning based on the ability of nucleosomes to protect associated DNA from digestion by micrococcal nuclease. Protected fragments are sequenced to produce genome-wide maps of nucleosome localization.


Covalent Attachment of Tags to Capture Histones and Identify Turnover is an assay for measuring nucleosome turnover kinetics genome-wide by metabolically labelling histones and profiling labelled DNA using microarrays.

Hidden Markov Model

A statistical model in which internal states are not visible but the outputs of these states are, and the outputs can therefore be used to infer the internal states. This model can be used to determine biologically relevant states from ChIP-seq data sets.


A method for mapping the distribution of chromatin-associated proteins by fusing a protein of interest with E. coli DNA adenine methyltransferase (Dam), which methylates adenines proximal to the binding sites of a protein, thus circumventing the need for antibodies.

Giemsa band

Also known as a Gband. A characteristic banding pattern is obtained by treating chromosomes with Giemsa stain. The intensity of Giemsa staining is correlated with genomic features. For instance, dark Giemsa bands usually are AT rich, have low gene density and have higher densities of repeat elements.

Polycomb body

A discrete nuclear focus containing Polycomb proteins and their silenced target genes. Polycomb bodies have been observed in D. melanogaster and human cells by imaging and in situ hybridization.


Chromosome conformation capture is a method to map chromosome interactions locally. It relies on an increased frequency of intramolecular ligation between fragments in close three-dimensional proximity in the nucleus.

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Zhou, V., Goren, A. & Bernstein, B. Charting histone modifications and the functional organization of mammalian genomes. Nat Rev Genet 12, 7–18 (2011).

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