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  • Review Article
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Nuclear receptor crosstalk — defining the mechanisms for therapeutic innovation

Nature Reviews Endocrinology volume 16, pages 363–377 (2020)Cite this article

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Abstract

Nuclear receptor crosstalk can be defined as the interplay between different nuclear receptors or between their overlapping signalling pathways. A subset of nuclear receptors (such as PPARs and RARs) engage in the formation of well-characterized ‘typical’ heterodimers with RXR. ‘Atypical’ heterodimers (such as GR with PPARs, or PPAR with ERR) might form a novel class of physical complexes that might be more transient in nature. These heterodimers might harbour strong transcriptional flexibility, with no strict need for DNA binding of both partners. Direct crosstalk could stem from a pairwise physical association between atypical nuclear receptor heterodimers, either via pre-existing interaction pairs or via interactions that are newly induced with small molecules; such crosstalk might constitute an uncharted space to target nuclear receptor physiological and/or pathophysiological actions. In this Review, we discuss the emerging aspects of crosstalk in the nuclear receptor field and present various mechanistic crosstalk modes with examples that support applicability of the atypical heterodimer concept. Stabilization or disruption, in a context-dependent or cell type-dependent manner, of these more transient heterodimers is expected to fuel unprecedented translational approaches to yield novel therapeutic agents to treat major human diseases with higher precision.

Key points

  • Nuclear receptors are versatile transcription factors of which most members can, to various extents, be ligand-modulated, which renders them highly susceptible to external control over their gene regulatory activities.

  • Atypical, probably more transient, nuclear receptor heterodimerization can influence particular subsets of genes and hence can affect gene expression patterns in distinct ways.

  • Broad mechanistic insights into the contribution of atypical nuclear receptor heterodimers to unique gene-modulatory events are lacking.

  • Molecular modulation of atypical nuclear receptor pairs might serve as novel avenues for ground-breaking drug development.

  • Targeting atypical heterodimers might lead to innovative and selective therapeutics with reduced side effects.

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Fig. 1: NR functional domain organization and most relevant regulatory functions.
Fig. 2: Visual representation of the atypical heterodimerization concept.
Fig. 3: Various modes of upstream pathway crosstalk mechanisms, indirectly influencing downstream gene transcription patterns.
Fig. 4: Conceptual and proven modes of NR crosstalk mechanisms at the DNA level.

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Acknowledgements

The authors thank W. Zwart for his valuable comments on the technology-oriented perspectives section. The authors apologize to colleagues who made a contribution to the nuclear receptor heterodimer field, and whose valuable work we might have inadvertently overlooked or could not include due to space constraints. S.J.D. is supported by a BOF-UGent postdoctoral grant (2019–2021). L.B. is supported by the Dutch Ministry of Education, Culture and Science through the Gravity program (024.001.035). E.E.-P. is supported by the Spanish Ministry of Science (BFU2017-86906-R; SAF2017-71878-REDT), CaixaImpulse Programme-La Caixa (CI18-0018) and Generalitat of Catalunya AGAUR-FEDER-2018 LLAVOR-0003. K.D.B. is supported by FWO-Vlaanderen (G031016N, 1503718N) and VIB (C0301). D.C. is supported by a research project funded by “Stand up to Cancer” (Kom op tegen Kanker, STI.VLK.2018.0019.01).

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Authors and Affiliations

  1. Translational Nuclear Receptor Research, VIB Center for Medical Biotechnology, UGent Department of Biomolecular Medicine, Gent, Belgium

    Karolien De Bosscher, Sofie J. Desmet & Dorien Clarisse

  2. Laboratory of Structural Biology, Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine (IBUB) of the University of Barcelona (UB), Barcelona, Spain

    Eva Estébanez-Perpiña

  3. Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Technische Universiteit Eindhoven, Eindhoven, Netherlands

    Luc Brunsveld

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Glossary

Cistromes

A term derived from ‘cistr’ (from cistron) and ‘ome’ (from genome), and is defined as the set of cis-acting targets of a trans-acting factor on a genome-wide scale.

Squelching

The phenomenon of a competition between transcription factors for a limited amount of common interacting proteins in a cell, with the functional consequence that the transcription factors in a given cell interfere with the activity of each other.

Re-chromatin immunoprecipitation sequencing (ChIP-seq) analysis

A technique whereby specific protein-bound chromatin fragments are first enriched with an antibody against one transcription factor (for example, a nuclear receptor), after which this enriched fraction is used to immune-precipitate protein partners on specific DNA fragments via enrichment with a second antibody (for example, against a second nuclear receptor). Sequencing of the isolated DNA fragments reveals genome-wide binding sites for which heterodimer binding becomes more likely.

ChIPexo

A technique where exonuclease is used to trim pulled-down chromatin to reduce the chance of detecting nearby protein–DNA binding events in the absence of a physical interaction at the DNA response element of interest.

Interactomes

The whole set of molecular interactions in cells, more specifically, the physical interactions among molecules.

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De Bosscher, K., Desmet, S.J., Clarisse, D. et al. Nuclear receptor crosstalk — defining the mechanisms for therapeutic innovation. Nat Rev Endocrinol 16, 363–377 (2020). https://doi.org/10.1038/s41574-020-0349-5

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