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Current challenges in understanding the role of enhancers in disease

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.

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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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