In vivo regulation of human skeletal muscle gene expression by thyroid hormone - PubMed (original) (raw)

In vivo regulation of human skeletal muscle gene expression by thyroid hormone

Karine Clément et al. Genome Res. 2002 Feb.

Abstract

Thyroid hormones are key regulators of metabolism that modulate transcription via nuclear receptors. Hyperthyroidism is associated with increased metabolic rate, protein breakdown, and weight loss. Although the molecular actions of thyroid hormones have been studied thoroughly, their pleiotropic effects are mediated by complex changes in expression of an unknown number of target genes. Here, we measured patterns of skeletal muscle gene expression in five healthy men treated for 14 days with 75 microg of triiodothyronine, using 24,000 cDNA element microarrays. To analyze the data, we used a new statistical method that identifies significant changes in expression and estimates the false discovery rate. The 381 up-regulated genes were involved in a wide range of cellular functions including transcriptional control, mRNA maturation, protein turnover, signal transduction, cellular trafficking, and energy metabolism. Only two genes were down-regulated. Most of the genes are novel targets of thyroid hormone. Cluster analysis of triiodothyronine-regulated gene expression among 19 different human tissues or cell lines revealed sets of coregulated genes that serve similar biologic functions. These results define molecular signatures that help to understand the physiology and pathophysiology of thyroid hormone action.

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Figures

Figure 1

Figure 1

Impact of thyroid hormone on genes grouped in functional categories. Information on gene function was obtained from Gene Ontology annotations for 6331 cDNAs represented on the microarray. Among the genes regulated by thyroid hormone, information was available for 257 cDNAs. The cDNAs were classified into the functional categories defined in Table 1. Bars represent percentages in each category.

Figure 2

Figure 2

Two-dimensional clustering of 19 tissue experiments and 403 transcripts, which showed variation after triiodothyronine treatment. The set of genes were selected from the data matrix provided by the hybridization of 19 human tissues and cell lines to a common reference pool. Experiments and responsive genes were grouped by hierarchical clustering after centering the log2 ratios on the mean for all experiments. Each row represents a single gene and each column an experimental sample. For each sample, the ratio of the abundance of the transcripts of each gene to the mean abundance across all experiments is represented by the color of the corresponding cell in the matrix file. (green boxes) Transcript levels lower than the mean. (red boxes) Transcript levels higher than the mean. (black boxes) transcript level equal to the mean. (gray lines) missing data. Each node of the gene dendrogram was analyzed, and we focused on sets of genes clustered by functions. The upper dendrogram shows similarities in the expression pattern between tissues and cell lines. (A) Protein turnover cluster. (B) Energy metabolism cluster.

Figure 2

Figure 2

Two-dimensional clustering of 19 tissue experiments and 403 transcripts, which showed variation after triiodothyronine treatment. The set of genes were selected from the data matrix provided by the hybridization of 19 human tissues and cell lines to a common reference pool. Experiments and responsive genes were grouped by hierarchical clustering after centering the log2 ratios on the mean for all experiments. Each row represents a single gene and each column an experimental sample. For each sample, the ratio of the abundance of the transcripts of each gene to the mean abundance across all experiments is represented by the color of the corresponding cell in the matrix file. (green boxes) Transcript levels lower than the mean. (red boxes) Transcript levels higher than the mean. (black boxes) transcript level equal to the mean. (gray lines) missing data. Each node of the gene dendrogram was analyzed, and we focused on sets of genes clustered by functions. The upper dendrogram shows similarities in the expression pattern between tissues and cell lines. (A) Protein turnover cluster. (B) Energy metabolism cluster.

Figure 3

Figure 3

Summary of thyroid hormone regulation of gene expression in human skeletal muscle. The 14-day treatment with triiodothyronine induces direct and indirect effects on gene transcription. The hormone regulates genes with a wide range of cellular functions. Post-transcriptional regulation of protein expression also may contribute to the physiological and pathological action of thyroid hormone.

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