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Comprehensive study of nuclear receptor DNA binding provides a revised framework for understanding receptor specificity

Author

Listed:
  • Ashley Penvose

    (Boston University
    Boston University)

  • Jessica L. Keenan

    (Boston University
    Boston University)

  • David Bray

    (Boston University
    Boston University)

  • Vijendra Ramlall

    (Boston University
    Boston University)

  • Trevor Siggers

    (Boston University
    Boston University
    Boston University)

Abstract

The type II nuclear receptors (NRs) function as heterodimeric transcription factors with the retinoid X receptor (RXR) to regulate diverse biological processes in response to endogenous ligands and therapeutic drugs. DNA-binding specificity has been proposed as a primary mechanism for NR gene regulatory specificity. Here we use protein-binding microarrays (PBMs) to comprehensively analyze the DNA binding of 12 NR:RXRα dimers. We find more promiscuous NR-DNA binding than has been reported, challenging the view that NR binding specificity is defined by half-site spacing. We show that NRs bind DNA using two distinct modes, explaining widespread NR binding to half-sites in vivo. Finally, we show that the current models of NR specificity better reflect binding-site activity rather than binding-site affinity. Our rich dataset and revised NR binding models provide a framework for understanding NR regulatory specificity and will facilitate more accurate analyses of genomic datasets.

Suggested Citation

  • Ashley Penvose & Jessica L. Keenan & David Bray & Vijendra Ramlall & Trevor Siggers, 2019. "Comprehensive study of nuclear receptor DNA binding provides a revised framework for understanding receptor specificity," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10264-3
    DOI: 10.1038/s41467-019-10264-3
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    Cited by:

    1. Indranil Paul & Dante Bolzan & Ahmed Youssef & Keith A. Gagnon & Heather Hook & Gopal Karemore & Michael U. J. Oliphant & Weiwei Lin & Qian Liu & Sadhna Phanse & Carl White & Dzmitry Padhorny & Sergei, 2023. "Parallelized multidimensional analytic framework applied to mammary epithelial cells uncovers regulatory principles in EMT," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    2. Devesh Bhimsaria & José A. Rodríguez-Martínez & Jacqui L. Mendez-Johnson & Debostuti Ghoshdastidar & Ashwin Varadarajan & Manju Bansal & Danette L. Daniels & Parameswaran Ramanathan & Aseem Z. Ansari, 2023. "Hidden modes of DNA binding by human nuclear receptors," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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