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Integration site selection by retroviruses and transposable elements in eukaryotes

Nature Reviews Genetics volume 18, pages 292–308 (2017)Cite this article

Subjects

Key Points

  • The non-random distribution of transposable elements (TEs) in eukaryotic genomes is the consequence of both TE integration site preferences and post-integration selection processes.

  • Next-generation sequencing approaches and experimentally induced de novo TE mobilization are pivotal for investigating the mechanisms of TE integration site preference.

  • Chromatin structure and spatial organization in the nucleus contribute to the efficiency and/or selectivity of TE integration.

  • Mobilization machineries are often tethered to specific chromatin states by a variety of host factors that determine the favoured insertion sites.

  • Target site preference is part of TE–host co-adaptation strategies that lead to TE repression or reactivation, which potentially results in rapid host adaptation or pathogenicity.

Abstract

Transposable elements and retroviruses are found in most genomes, can be pathogenic and are widely used as gene-delivery and functional genomics tools. Exploring whether these genetic elements target specific genomic sites for integration and how this preference is achieved is crucial to our understanding of genome evolution, somatic genome plasticity in cancer and ageing, host–parasite interactions and genome engineering applications. High-throughput profiling of integration sites by next-generation sequencing, combined with large-scale genomic data mining and cellular or biochemical approaches, has revealed that the insertions are usually non-random. The DNA sequence, chromatin and nuclear context, and cellular proteins cooperate in guiding integration in eukaryotic genomes, leading to a remarkable diversity of insertion site distribution and evolutionary strategies.

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Figure 1: Accumulation of transposable elements in genomes results from the balance between transposable element integration site preference and post-integration selection processes.
Figure 2: Principles of insertion profiling by deep sequencing.
Figure 3: Extended tethering scheme.
Figure 4: Models of the regulation of integration site selection.
Figure 5: Multiple factors influence integration site selection.

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Acknowledgements

The authors apologize to many colleagues who have made significant contributions to the field, but whose work could not be cited or discussed owing to space limitations. The authors are grateful to M. Lavigne, A. Doucet and J. Recht for critical reading of the manuscript. This work was supported by grants to G.C. from the Fondation ARC pour la Recherche sur le Cancer (Projet Fondation ARC, 20141201838); the Fondation pour la Recherche Médicale (FRM; DEP20131128533); the French Government (Agence Nationale Recherche (ANR)) through 'Investments for the Future' (LABEX SIGNALIFE, ANR-11- LABX-0028-01) and through the generic call project RETROMET (ANR-16-CE12-0020); the Cancéropôle Provence-Alpes-Côte d'Azur (Projet Emergence), Centre National de la Recherche Scientifique (CNRS; GDR 3546); and the University Hospital Federation (FHU) OncoAge. T.S. was supported by a joint Erasmus Mundus Mobility with Asia fellowship between Université Côte d'Azur, France, and University of Dhaka, Bangladesh. The work of P.L. is supported by intramural funding from CNRS, the Université Paris Diderot and the Institut National de la Santé et de la Recherche Médicale, and by grants from the Canceropôle Ile de France (2015–1 EMERG-24), Fondation ARC pour la Recherche sur le Cancer (PJA 20151203412), the ANR through the initiatives d'excellence (Idex ANR-11-IDEX-0005-02), the Labex Who am I? ANR11-LABX-0071) and the generic call project NiCiTy (ANR-13-BSV3-0012). The work of A.Z. is supported by intramural funding from Conservatoire National des Arts et Métiers, France.

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  1. Tania Sultana and Alessia Zamborlini: These authors contributed equally to this work.

Authors and Affiliations

  1. Université Côte d'Azur, INSERM, CNRS, IRCAN, 28 Ave de Valombrose, 06107, Nice Cedex 02, France

    Tania Sultana & Gael Cristofari

  2. Sorbonne Paris Cité, Université Paris Diderot, Institut National de la Santé et de la Recherche Médicale U944, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7212, Institut Universitaire d'Hématologie, Hôpital St. Louis, 1 Ave Claude Vellefaux, Paris, 75010, France

    Alessia Zamborlini & Pascale Lesage

  3. Laboratoire Pathologie et Virologie Moléculaire, Conservatoire National des Arts et Métiers, 292 Rue Saint-Martin, Paris, 75003, France

    Alessia Zamborlini

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Glossary

Cis-regulatory sequences

Sequences within a DNA or RNA molecule that regulate transactions involving the same nucleic acid (for example, transcription, splicing, polyadenylation, translation, degradation, replication and recombination).

Selection

A process by which biological and environmental constraints eliminate — or favour the reproduction of — organisms or cells with a given phenotype.

Tropism

In the context of this Review, the propensity of a transposable element to target specific genomic regions. The term can also refer to the preferred cell type or tissue of an infectious microorganism.

Accessions

Strains from a plant variety that has been propagated from seeds collected from a single individual in the wild. Accessions are typically given the name of the location from which the seeds were collected.

Euchromatic

A term that describes a type of chromatin that is less tightly packed and is enriched in transcribed genes.

Closed mitosis

A cell division in which the nuclear envelope stays intact.

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Sultana, T., Zamborlini, A., Cristofari, G. et al. Integration site selection by retroviruses and transposable elements in eukaryotes. Nat Rev Genet 18, 292–308 (2017). https://doi.org/10.1038/nrg.2017.7

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