Thyroid hormone (T3) has a profound effect on mitochondrial biogenesis. T3-regulated gene expression is mediated by thyroid hormone receptor (TR) binding to thyroid hormone response elements (TREs). In concert with the action of various coactivators and corepressors this interaction leads to a modulation of the chromatin structure and subsequently to a modulation of gene expression of adjacent target genes. However, as numerous genes are endogenously regulated by T3, and a TRE appears to be absent in their regulatory elements, a TRindependent pathway of T3-mediated gene regulation is likely. In this review, we discuss the direct mechanisms of TR-dependent regulation of gene expression on the nuclear and mitochondrial genome by T3. We also summarise recent observations on an indirect mechanism of T3 action via intermediate factor(s). We discuss the regulation of nuclear respiratory factor 1 (NRF-1) and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1a) by T3, suggesting NRF-1 and PGC-1a as attractive candidates for an intermediate factor of T3 action in vivo.

Thyroid hormone (T3) is essential for normal development, differentiation and metabolic balance. Only a limited number of T3-target genes have been identified so far and their complex regulation pattern is poorly understood. We performed cDNA expression array hybridisation to identify T3-regulated genes and to investigate their expression pattern after various time points in vivo. Radioactively labelled cDNA was prepared from hepatic RNA of hypothyroid and hyperthyroid rats 6, 24 and 48 h after the administration of T3. Labelled cDNA probes were hybridised to rat Atlas Arrays. Twenty-three of 588 genes were shown to be differentially regulated, 18 of which were previously not known to be regulated by T3. The expression of 19 genes was verified by independent northern blot hybridisation. Two different expression time courses of T3 expression were observed. In a first expression profile ('early' expression) the transcription level of the target genes rises within 6 h, drops by 24 h and increases again within 48 h after the administration of T3. In a second expression profile ('late' expression) the mRNA level rose in the first 6 h and rose further by 48 h, indicating an additional regulation mechanism. Nuclear respiratory factor (NRF)-1 and peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1), but not NRF-2, were up-regulated within 6 h after T3 administration, suggesting NRF-1 and/or PGC-1 as key regulators for mediating the 'late' expression pattern.

Here, we describe the cloning and further characterization of chicken ARBP, an abundant nuclear protein with a high affinity for MAR/SARs. Surprisingly, ARBP was found to be homologous to the rat protein MeCP2, previously identified as a methyl-CpG-binding protein. A region spanning 125 amino acids in the N-terminal halves is 96.8% identical between chicken ARBP and rat MeCP2. A deletion mutation analysis using Southwestern and band shift assays identified this highly conserved region as the MAR DNA binding domain. Alignment of chicken ARBP with rat and human MeCP2 proteins revealed six trinucleotide amplifications generating up to 34-fold repetitions of a single amino acid. Because MeCP2 was previously localized to pericentromeric heterochromatin in mouse chromosomes, we analyzed the in vitro binding of ARBP to various repetitive sequences. In band shift experiments, ARBP binds to two chicken repetitive sequences as well as to mouse satellite DNA with high affinity similar to that of its binding to chicken lysozyme MAR fragments. In mouse satellite DNA, use of several footprinting techniques characterized two high-affinity binding sites, whose sequences are related to the ARBP binding site consensus in the chicken lysozyme MAR (5-GGTGT-3). Band shift experiments indicated that methylation increased in vitro binding of ARBP to mouse satellite DNA twoto fivefold. Our results suggest that ARBP/MeCP2 is a multifunctional protein with roles in loop domain organization of chromatin, the structure of pericentromeric heterochromatin, and DNA methylation.

Please cite this article as: Weitzel, J.M., Alexander Iwen, K., Coordination of mitochondrial biogenesis by thyroid hormone, Molecular and Cellular Endocrinology Molecular and Cellular Endocrinology (2011), doi: 10.1016/j.mce. 2011 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.