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Current challenges in understanding the role of enhancers in disease

Nature Structural & Molecular Biology volume 29, pages 1148–1158 (2022)Cite this article

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Abstract

Enhancers play a central role in the spatiotemporal control of gene expression and tend to work in a cell-type-specific manner. In addition, they are suggested to be major contributors to phenotypic variation, evolution and disease. There is growing evidence that enhancer dysfunction due to genetic, structural or epigenetic mechanisms contributes to a broad range of human diseases referred to as enhanceropathies. Such mechanisms often underlie the susceptibility to common diseases, but can also play a direct causal role in cancer or Mendelian diseases. Despite the recent gain of insights into enhancer biology and function, we still have a limited ability to predict how enhancer dysfunction impacts gene expression. Here we discuss the major challenges that need to be overcome when studying the role of enhancers in disease etiology and highlight opportunities and directions for future studies, aiming to disentangle the molecular basis of enhanceropathies.

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Fig. 1: Different mechanisms of enhancer function and dysfunction.
Fig. 2: Challenges to unravel enhancer-associated diseases.

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Acknowledgements

All authors are members of the EU-funded Innovative Training Network ‘Molecular Basis of Human Enhanceropathies’ (Enhpathy, www.enhpathy.eu) and received funding from the Horizon 2020 research and innovation program under Marie Sklodowska-Curie grant agreement no. 860002. The Enhpathy network has set up a multidisciplinary scientific consortium in the continuum of basic, translational and clinical research on enhancers and associated diseases.

Author information

Author notes

  1. These authors contributed equally: Judith Barbara Zaugg, Pelin Sahlén, Robin Andersson, Salvatore Spicuglia.

Authors and Affiliations

  1. European Molecular Biology Laboratory, Heidelberg, Germany

    Judith Barbara Zaugg

  2. Science for Life Laboratory, KTH – Royal Institute of Technology, Solna, Sweden

    Pelin Sahlén

  3. Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, Copenhagen, Denmark

    Robin Andersson

  4. The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Robin Andersson & Susanne Mandrup

  5. Department of Hemato-oncology, Institute of Molecular Genetics of the CAS, Prague, Czech Republic

    Meritxell Alberich-Jorda

  6. Childhood Leukaemia Investigation Prague, Department of Pediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University in Prague, University Hospital Motol, Prague, Czech Republic

    Meritxell Alberich-Jorda

  7. Hubrecht Institute-KNAW, Oncode Institute and University Medical Center Utrecht, Utrech, Netherlands

    Wouter de Laat

  8. Laboratory of Systems Biology and Genetics, Institute of Bio-engineering, School of Life Sciences, EPFL, Lausanne, Switzerland

    Bart Deplancke

  9. Centre for Genomic Regulation, the Barcelona Institute of Science and Technology, Barcelona, Spain

    Jorge Ferrer

  10. Centro de Investigación Biomédica en red Diabetes y enfermedades metabólicas asociadas (CIBERDEM), Madrid, Spain

    Jorge Ferrer

  11. Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

    Jorge Ferrer

  12. Functional Genomics and Metabolism Research Unit, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark

    Susanne Mandrup

  13. IEO, European Institute of Oncology – IRCCS, Milan, Italy

    Gioacchino Natoli

  14. Laboratory of Functional and Structural Genomics, Centre of New Technologies, University of Warsaw, Warsaw, Poland

    Dariusz Plewczynski

  15. Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC), CSIC/University of Cantabria, Santander, Spain

    Alvaro Rada-Iglesias

  16. TAGC, UMR 1090, Aix-Marseille University, INSERM, Marseille, France

    Salvatore Spicuglia

  17. Equipe Labellisée, LIGUE Contre le Cancer, Marseille, France

    Salvatore Spicuglia

Authors
  1. Judith Barbara Zaugg
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  2. Pelin Sahlén
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  3. Robin Andersson
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  4. Meritxell Alberich-Jorda
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  5. Wouter de Laat
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  6. Bart Deplancke
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  7. Jorge Ferrer
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  8. Susanne Mandrup
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  9. Gioacchino Natoli
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  10. Dariusz Plewczynski
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  11. Alvaro Rada-Iglesias
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  12. Salvatore Spicuglia
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Corresponding author

Correspondence to Salvatore Spicuglia.

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Zaugg, J.B., Sahlén, P., Andersson, R. et al. Current challenges in understanding the role of enhancers in disease. Nat Struct Mol Biol 29, 1148–1158 (2022). https://doi.org/10.1038/s41594-022-00896-3

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