Multi-tissue gene-expression analysis in a mouse model of thyroid hormone resistance
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
Genome Biology 2004, 5:R31 doi:Published: 29 April 2004
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.
We analyzed transcript levels in cerebellum, heart and white adipose tissue from a knock-in mouse (TRβPV/PV mouse) that harbors a human mutation (referred to as PV) and faithfully reproduces human RTH. Because TRβPV/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 TRβPV/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 TRβPV/PV mice were repressed in T3-treated wild-type mice and upregulated in TRβPV/PV mice, suggesting the inappropriate activation of T3-suppressed genes in RTH.
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.