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

Ashley Penvose, Jessica L. Keenan, David Bray, Vijendra Ramlall and Trevor Siggers ()
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Ashley Penvose: Boston University
Jessica L. Keenan: Boston University
David Bray: Boston University
Vijendra Ramlall: Boston University
Trevor Siggers: Boston University

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10264-3

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