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Department of Endocrinology and Metabolism, Academic Medical Centre, F5-171, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
¹ Department of Cell Biology, The Scripps Research Institute, MB111, Maildrop MB-24, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA

(Requests for offprints should be addressed to O Bakker; Email: o.bakker{at}amc.uva.nl)

Transcripts derived from the thyroid hormone receptor (TR) gene are alternatively spliced resulting in a functional receptor TR1 and a non-T₃-binding variant TR2 that can exert a dominant negative effect on the transactivation functions of other TRs. There is evidence that the ratio of TR isoform transcripts can be modulated and here, we investigate whether the PPAR co-activator (PGC-1) has an effect on this splicing process. PGC-1 was discovered not only as a transcriptional co-activator, but also has certain motifs characteristic of splicing factors. We demonstrate that PGC-1 alters the ratio of endogenously expressed TR isoform transcripts in HepG2 cells, by decreasing TR1 mRNA levels twofold. This change in isoform ratio is accompanied by a decrease in 5'-deiodinase expression, whereas no differences were found in TRß1 expression. Deletion of the RNA-processing domain of PGC-1 abrogated the effect on the TR splicing, whereas expression of only the RNA-processing domain favored TR1 expression. PGC-1 showed a similar effect on the splicing of a TR minigene containing only the last four exons and introns of the TR gene. These data suggest that PGC-1 is involved in the RNA processing of TR transcripts.