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Novel Mode of Deoxyribonucleic Acid Recognition by Thyroid Hormone Receptors: Thyroid Hormone Receptor ß-Isoforms Can Bind as Trimers to Natural Response Elements Comprised of Reiterated Half-Sites

Section of Microbiology, Division of Biological Sciences, University of California, Davis, California 95616

Address all correspondence and requests for reprints to: Martin L. Privalsky, Section of Microbiology, Division of Biological Sciences, One Shields Avenue, University of California at Davis, Davis, California 95616. E-mail: mlprivalsky{at}ucdavis.edu.

Thyroid hormone receptors (TRs) regulate gene expression by binding to specific DNA sequences, denoted thyroid hormone response elements (TREs). The accepted paradigm for TRs proposes that they bind as homo- or heterodimers to TREs comprised of two AGGTCA half-site sequences. In the prototypic TRE, these half-sites are arranged as direct repeats separated by a four-base spacer. This dimeric model of TR binding, derived from analysis of artificial DNA sequences, fails to explain why many natural TREs contain more than two half-sites. Therefore, we investigated the ability of different TR isoforms to bind to TREs possessing three or more half-sites. We report that the TRß isoforms (TRß0, TRß1, TRß2), but not TR1, can bind to reiterated DNA elements, such as the rat GH-TRE, as complexes trimeric or greater in size. The TRß0 isoform, in particular, formed homo- and heterotrimers (with the retinoid X receptor) with high efficiency and cooperativity, and TRß0 preferentially used reporters containing these reiterated elements to drive gene expression in vivo. Our data demonstrate that TRß isoforms can form multimeric receptor complexes on appropriately reiterated DNA response elements, providing a functional distinction between the TR isoforms and an explanation for TREs possessing three or more half-sites.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα  |  TRβ  |  RXRα

Coregulators:   AIB1  |  NCOR  |  SMRT

Ligands:   Thyroid hormone

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