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  • Review Article
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Replication and transcription: Shaping the landscape of the genome

Nature Reviews Genetics volume 6, pages 669–677 (2005)Cite this article

Key Points

  • DNA replication in mammalian nuclei is carried out in specialized structures that are known as replication factories. Throughout S phase, these factories assemble dynamically, and replicons that are located in their vicinity are recruited to the replication sub-compartment.

  • GC-rich, gene-dense regions tend to replicate early in S phase, whereas AT-rich regions that are usually gene-poor replicate late. In many cases, expressed genes replicate early in S phase and silent genes replicate late, but there are many exceptions to this rule.

  • Early replication timing is probably determined by epigenetic information and chromatin structure rather than by individual gene expression per se. Gene expression does not seem to be a direct consequence of early replication.

  • Transcription is highly compartmentalized in mammalian nuclei. Nascent transcription by RNA polymerase II occurs in foci that are known as transcription factories. Cells contain very few transcription factories compared with the number of active genes.

  • Most 'active' genes are not continuously transcribed, but undergo transcription cycles. Modulation of expression might occur by changing the frequency or duration of the 'on' state versus the 'off' state.

  • On activation, genes migrate to pre-assembled transcription factories that are shared with other actively transcribed genes.

  • In higher eukaryotes approximately 15% of the genome is transcribed. Most transcribed genomic regions are intergenic sequences.

  • The finding that most of the genome is transcribed indicates that transcription factories are principal focal points for the nuclear organization of the genome.

  • The clustering of genes around functional sites in the nucleus might impose selective pressures on the organization of genes and regulatory elements at the primary sequence level, thereby contributing to the observed clustering of highly expressed genes in the genome.

Abstract

As the relationship between nuclear structure and function begins to unfold, a picture is emerging of a dynamic landscape that is centred on the two main processes that execute the regulated use and propagation of the genome. Rather than being subservient enzymatic activities, the replication and transcriptional machineries provide potent forces that organize the genome in three-dimensional nuclear space. Their activities provide opportunities for epigenetic changes that are required for differentiation and development. In addition, they impose physical constraints on the genome that might help to shape its evolution.

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Figure 1: Patterns of replication foci in S phase cells.
Figure 2: Transcription factories.
Figure 3: A chromatin hub.
Figure 4: Organizer factory.
Figure 5: Transcription factory model.

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Acknowledgements

The authors would like to thank A. Horton, P. Varga-Wiesz, W. Reik and A. Corcoran for helpful discussions. We are also grateful to S. Gasser for the yeast chromatin dynamics movie and D. Dimitrova for DNA replication micrographs. J.A.M. is supported by a Natural Sciences and Engineering Research Council of Canada postdoctoral fellowship. P.F. is a Senior Fellow of the Medical Research Council (MRC) and is supported by the MRC and Biotechnology and Biological Sciences Research Council, UK.

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  1. Laboratory of Chromatin and Gene Expression, The Babraham Institute, Babraham Research Campus, Cambridge, CB2 4AT, United Kingdom

    Lyubomira Chakalova, Emmanuel Debrand, Jennifer A. Mitchell, Cameron S. Osborne & Peter Fraser

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  1. Lyubomira Chakalova
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  2. Emmanuel Debrand
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  3. Jennifer A. Mitchell
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Correspondence to Peter Fraser.

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DATABASES

Entrez Gene

Air

CFTR

Eraf

Hbb

HoxB

Xist

Supplementary Information

Glossary

NUCLEAR LAMINA

A scaffold of proteins — mainly lamin A/C and B — that are predominantly found in the nuclear periphery associated with the inner surface of the nuclear membrane.

NUCLEOLUS

A highly organized nuclear organelle that is the site of ribosomal RNA processing and ribosome assembly.

NUCLEAR MATRIX

A three-dimensional filamentous protein network in the nucleus that remains intact after high salt extraction.

LONG INTERSPERSED NUCLEAR ELEMENTS

A class of repeat sequences.

REPLICATION ORIGINS

DNA sequences at which DNA replication is initiated.

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.

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Chakalova, L., Debrand, E., Mitchell, J. et al. Replication and transcription: Shaping the landscape of the genome. Nat Rev Genet 6, 669–677 (2005). https://doi.org/10.1038/nrg1673

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