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Dynamic genome architecture in the nuclear space: regulation of gene expression in three dimensions

Key Points

  • Chromatin is mobile in the cell nucleus and undergoes movements that are best described as constrained diffusion.

  • The extent of chromatin mobility is maximal in the early G1 phase of the cell cycle and can change depending on the differentiation status of the cell.

  • Chromatin mobility is limited by structural constraints, as reflected in the territorial organization of chromosomes, the gene-density-related polarity of chromosome territories and the clustering of active and inactive chromatin in the nucleus.

  • Chromatin movements away from the nuclear periphery or constitutive heterochromatin have been associated with gene activity in certain mammalian cell types.

  • As a result of chromatin mobility, genomic regions interact with each other in the nucleus, a phenomenon that is referred to as 'gene kissing'. Recently, cases in which gene kissing has an important role in transcriptional regulation have been reported.

  • Recent technological advances have allowed the large-scale identification of interacting loci. Initial results indicate that gene–gene interactions are driven in large part by the surrounding chromatin features (for example, transcriptional activity, histone code and gene content), rather than by a specific gene function being shared by the interacting partners.

Abstract

The regulation of gene expression is mediated by interactions between chromatin and protein complexes. The importance of where and when these interactions take place in the nucleus is currently a subject of intense investigation. Increasing evidence indicates that gene activation or silencing is often associated with repositioning of the locus relative to nuclear compartments and other genomic loci. At the same time, however, structural constraints impose limits on chromatin mobility. Understanding how the dynamic nature of the positioning of genetic material in the nuclear space and the higher-order architecture of the nucleus are integrated is therefore essential to our overall understanding of gene regulation.

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Figure 1: Organization of the mammalian cell nucleus.
Figure 2: Gene kissing.
Figure 3: A model of structural constraints on chromatin mobility and gene–gene interactions.
Figure 4: Chromatin mobility and principles of nuclear organization.

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Acknowledgements

We thank F. Bantignies and H. Albiez for help with figures and for discussing the manuscript. T. Cheutin was supported by the Centre National de la Recherche Scientifique. G.C. was supported by grants from the Centre National de la Recherche Scientifique, the Human Frontier Science Program Organization, the European Union FP 6 (Network of Excellence 'The Epigenome' and STREP '3D Genome'), the Ministère de la Recherche (ACI BCMS 2004), and by the Agence Nationale de la Recherche. C.L. was supported by fellowships from the Humboldt Stiftung and the Instituts de recherche en santé du Canada. T.C. was supported by grants from the Deutsche Forschungsgemeinschaft (SFB/Transregio 5) and T.C and M.C were supported by the Wilhelm-Sanderstiftung.

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Glossary

PML bodies

Nuclear structures that are enriched for the promyeolocytic leukaemia (PML) RING-finger protein and are implicated in transcriptional regulation, viral pathogenicity, tumour suppression, apoptosis and DNA repair.

Cajal bodies

Spherical structures that are involved in the processing of nuclear RNA. Marker proteins include p80 coilin and the survival of motor neuron (SMN) protein.

Nuclear speckles

Irregular structures that contain high concentrations of splicing factors and small nuclear ribonucleoprotein particles (snRNPs).

Two-photon microscopy

An imaging technique in which a fluorochrome that would normally be excited by a single photon is stimulated quasi-simultaneously by two photons of lower energy. This allows reduced light scattering and less photodamage of the sample.

Sampling volume

The volume or area of a cell or an organelle in which fluorophores are excited or from which emitted photons are collected. Temporal resolution can be increased during imaging by decreasing sampling volume.

Fluorescence in situ hybridization

A technique in which a fluorescently labelled DNA probe is used to detect a particular chromosome or gene with the help of fluorescence microscopy.

GFP–lac repressor/lac operator system

A technology that allows the imaging of a DNA locus in living cells, which works on the basis of the high-affinity binding of a fluorescent lac repressor to an episomal or stably integrated array of lac operators.

Variegated expression

A mosaic pattern of gene expression that results from epigenetic modifications that are associated with the presence of heterochromatic sequences near euchromatic regions of the genome.

Polycomb group

A class of proteins, originally described in Drosophila melanogaster, that maintain the stable and heritable repression of several genes, including the homeotic genes.

X-inactivation centre

A genomic region (of 35–400 kb in mice) comprising genes and regulatory elements that are responsible for the cis inactivation of the entire X chromosome.

X-chromosome counting

A mechanism by which the cell detects the number of X chromosomes for each diploid set of autosomes. This process ensures that a single X chromosome is inactivated.

RNA FISH

A technique in which a fluorescently labelled nucleic-acid probe is used to detect cellular transcripts in situ. Probes that are complementary to intronic sequences will hybridize at the site of nuclear transcription.

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.

Imprinting control region

A genomic region that is subject to monoallelic DNA methylation during gametogenesis. This modification results in the differential activity of the paternal and maternal alleles.

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Lanctôt, C., Cheutin, T., Cremer, M. et al. Dynamic genome architecture in the nuclear space: regulation of gene expression in three dimensions. Nat Rev Genet 8, 104–115 (2007). https://doi.org/10.1038/nrg2041

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