Novel mode of deoxyribonucleic acid recognition by thyroid hormone receptors

Thyroid hormone receptor β-isoforms can bind as trimers to natural response elements comprised of reiterated half-sites

Brenda J. Mengeling, Fan Pan, Martin L. Privalsky

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

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 TRβ isoforms (TRβ0, TRβ1, TRβ2), but not TRα1, can bind to reiterated DNA elements, such as the rat GH-TRE, as complexes trimeric or greater in size. The TRβ0 isoform, in particular, formed homo- and heterotrimers (with the retinoid X receptor) with high efficiency and cooperatively, and TRβ0 preferentially used reporters containing these reiterated elements to drive gene expression in vivo. Our data demonstrate that TRβ 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.

Original languageEnglish (US)
Pages (from-to)35-51
Number of pages17
JournalMolecular Endocrinology
Volume19
Issue number1
DOIs
StatePublished - Jan 2005

Fingerprint

Thyroid Hormone Receptors
Response Elements
Thyroid Hormones
Protein Isoforms
DNA
Retinoid X Receptors
Gene Expression
Nucleic Acid Repetitive Sequences
DNA Sequence Analysis

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Cite this

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abstract = "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 TRβ isoforms (TRβ0, TRβ1, TRβ2), but not TRα1, can bind to reiterated DNA elements, such as the rat GH-TRE, as complexes trimeric or greater in size. The TRβ0 isoform, in particular, formed homo- and heterotrimers (with the retinoid X receptor) with high efficiency and cooperatively, and TRβ0 preferentially used reporters containing these reiterated elements to drive gene expression in vivo. Our data demonstrate that TRβ 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.",
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