Research

Multi-tissue gene-expression analysis in a mouse model of thyroid hormone resistance

Lance D Miller¹, Peter McPhie², Hideyo Suzuki³, Yasuhito Kato³, Edison T Liu¹ and Sheue-yann Cheng³

¹  Genome Institute of Singapore, Agency for Science, Technology and Research, 60 Biopolis Street, Singapore, 138672

²  National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA

³  Laboratory of Molecular Biology, National Cancer Institute, Bethesda, MD 20892-4264, USA

author email corresponding author email

Genome Biology 2004, 5:R31

Published:	29 April 2004

Subject areas: Medicine, Genetics, Genome studies, Molecular biology

Abstract

Background

Resistance to thyroid hormone (RTH) is caused by mutations of the thyroid hormone receptor β (TRβ) gene. To understand the transcriptional program underlying TRβ mutant-induced phenotypic expression of RTH, cDNA microarrays were used to profile the expression of 11,500 genes in a mouse model of human RTH.

Results

We analyzed transcript levels in cerebellum, heart and white adipose tissue from a knock-in mouse (TRβ^PV/PV mouse) that harbors a human mutation (referred to as PV) and faithfully reproduces human RTH. Because TRβ^PV/PV mice have elevated thyroid hormone (T3), to define T3-responsive genes in the context of normal TRβ, we also analyzed T3 effects in hyperthyroid wild-type gender-matched littermates. Microarray analysis revealed 163 genes responsive to T3 treatment and 187 genes differentially expressed between TRβ^PV/PV mice and wild-type littermates. Both the magnitude and gene make-up of the transcriptional response varied widely across tissues and conditions. We identified genes modulated in T3-dependent PV-independent, T3- and PV-dependent, and T3-independent PV-dependent pathways that illuminated the biological consequences of PV action in vivo. Most T3-responsive genes that were dysregulated in the heart and white adipose tissue of TRβ^PV/PV mice were repressed in T3-treated wild-type mice and upregulated in TRβ^PV/PV mice, suggesting the inappropriate activation of T3-suppressed genes in RTH.

Conclusions

Comprehensive multi-tissue gene-expression analysis uncovered complex multiple signaling pathways that mediate the molecular actions of TRβ mutants in vivo. In particular, the T3-independent mutant-dependent genomic response unveiled the contribution of a novel 'change-of-function' of TRβ mutants to the pathogenesis of RTH. Thus, the molecular actions of TRβ mutants are more complex than previously envisioned.