Key Points
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Contacts between distant genomic regions in the same or in different chromosomes are important in the regulation of gene expression, as highlighted by the activation of genes by chromatin contacts between promoters and enhancers that can lie hundreds of kb away.
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Chromatin contacts are currently measured by two main approaches: chromosome conformation capture (3C)-based techniques and nuclear imaging methods such as fluorescence in situ hybridization (FISH). Both approaches have caveats, and the field is ripe for further technical development.
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The formation of chromatin contacts is promoted by chromatin-binding proteins that can bind two or more genomic regions simultaneously. Such proteins include transcription factors, RNA and DNA polymerases, Polycomb repressive complexes and chromosomal scaffold proteins such as cohesin.
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Topologically associating domains (TADs) are genomic regions enriched with contacts within them. TADs have specific sizes and positions in the genome and are found in a wide range of metazoans. The factors and mechanisms that promote TAD formation are a matter of considerable debate.
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The three-dimensional organization of the genome also depends on the formation of chromatin contacts with nuclear domains and compartments such as the nuclear lamina and the nucleolus. Specific sets of chromatin contacts are formed within each chromosome, and between them and nuclear domains. The mechanisms that govern chromosome localization, volume and shape remain poorly understood.
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Many cellular processes such as division, differentiation and senescence, present challenges to the maintenance of nuclear organization, gene expression programs and cell identity. At the same time, they can also offer opportunities for chromatin remodelling and the reinforcement of gene expression patterns.
Abstract
The different cell types of an organism share the same DNA, but during cell differentiation their genomes undergo diverse structural and organizational changes that affect gene expression and other cellular functions. These can range from large-scale folding of whole chromosomes or of smaller genomic regions, to the re-organization of local interactions between enhancers and promoters, mediated by the binding of transcription factors and chromatin looping. The higher-order organization of chromatin is also influenced by the specificity of the contacts that it makes with nuclear structures such as the lamina. Sophisticated methods for mapping chromatin contacts are generating genome-wide data that provide deep insights into the formation of chromatin interactions, and into their roles in the organization and function of the eukaryotic cell nucleus.
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Change history
05 August 2015
In the original article, the following sentence was incorrect: “Histone marks associated with enhancers, such as histone 3 Lys4 monomethylation (H3K4me1), and with transcription repression, such as histone 3 Lys9 trimethylation (H3K9me3), were also enriched at TAD boundaries.2” The corrected sentence is as follows: “Histone marks associated with enhancers, such as histone 3 Lys4 monomethylation (H3K4me1), and with transcription repression, such as histone 3 Lys9 trimethylation (H3K9me3), were not found to be enriched at TAD boundaries.” This has been corrected in the online version of the article.
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Acknowledgements
The authors thank P. Sabbattini for providing the images shown in Fig. 4a. Work in N.D.'s laboratory is supported by the Medical Research Council, UK. A.P. thanks the Helmholtz Foundation for support.
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Relating chromatin contacts to gene regulation mechanisms (PDF 117 kb)
Glossary
- Chromatin immunoprecipitation
-
A method in which chromatin bound by a protein is immunoprecipitated with an antibody against that protein, to allow the extraction and analysis of the bound DNA by quantitative PCR or genome-wide sequencing.
- Nuclear lamina
-
A protein meshwork made of intermediate filaments (such as lamins) and membrane-associated proteins (such as emerin) that covers the inner nuclear membrane and is responsible for maintaining nuclear shape, organization and function.
- Heterochromatin
-
Highly condensed chromatin that shows dark staining. Constitutive heterochromatin remains in this state throughout the cell cycle. Facultative heterochromatin is cell-type-specific condensed chromatin that is often a feature of terminally differentiated cells.
- DNA adenine methyltransferase identification
-
A method based on expression of fusion proteins with bacterial Dam methylase, and detection of methylated DNA as a measure of its contact with the fusion protein.
- Cryoprotected cells
-
Cells that have been treated with a cryoproctectant to prevent structural damage during freezing.
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Pombo, A., Dillon, N. Three-dimensional genome architecture: players and mechanisms. Nat Rev Mol Cell Biol 16, 245–257 (2015). https://doi.org/10.1038/nrm3965
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DOI: https://doi.org/10.1038/nrm3965
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