title: Multi-tissue gene-expression analysis in a mouse model of thyroid hormone resistance.
abstract: BACKGROUND
  Resistance to thyroid hormone (RTH) is caused by mutations of the thyroid hormone receptor beta (TRbeta) gene. To understand the transcriptional program underlying TRbeta 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 (TRbetaPV/PV mouse) that harbors a human mutation (referred to as PV) and faithfully reproduces human RTH. Because TRbetaPV/PV mice have elevated thyroid hormone (T3), to define T3-responsive genes in the context of normal TRbeta, 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 TRbetaPV/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 TRbetaPV/PV mice were repressed in T3-treated wild-type mice and upregulated in TRbetaPV/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 TRbeta mutants in vivo. In particular, the T3-independent mutant-dependent genomic response unveiled the contribution of a novel 'change-of-function' of TRbeta mutants to the pathogenesis of RTH. Thus, the molecular actions of TRbeta mutants are more complex than previously envisioned.
authors.affiliation: 1Genome Institute of Singapore, Agency for Science, Technology and Research, 60 Biopolis Street, Singapore, 138672.
authors.forename: Lance D
authors.initials: LD
authors.lastname: Miller
authors.forename: Peter
authors.initials: P
authors.lastname: McPhie
authors.forename: Hideyo
authors.initials: H
authors.lastname: Suzuki
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Kato
authors.forename: Edison T
authors.initials: ET
authors.lastname: Liu
authors.forename: Sheue-yann
authors.initials: SY
authors.lastname: Cheng
mesh_terms: D000273:Adipose Tissue / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002531:Cerebellum / Q000737:chemistry / Q000378:metabolism; D016000:Cluster Analysis; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D005796:Genes / Q000502:physiology; D006801:Humans; D006980:Hyperthyroidism / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics* / Q000502:physiology; D010641:Phenotype; D015398:Signal Transduction / Q000235:genetics; D037042:Thyroid Hormone Receptors beta / Q000172:deficiency / Q000235:genetics; D018382:Thyroid Hormone Resistance Syndrome / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics; D014284:Triiodothyronine / Q000494:pharmacology / Q000502:physiology
chemical_list: D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine