Transcripts derived from the thyroid hormone receptor α (TRα) gene are alternatively spliced resulting in a functional receptor TRα1 and a non-T3-binding variant TRα2 that can exert a dominant negative effect on the transactivation functions of other TRs. There is evidence that the ratio of TRα isoform transcripts can be modulated and here, we investigate whether the PPARγ co-activator α (PGC-1α) has an effect on this splicing process. PGC-1α was discovered not only as a transcriptional co-activator, but also has certain motifs characteristic of splicing factors. We demonstrate that PGC-1α alters the ratio of endogenously expressed TRα isoform transcripts in HepG2 cells, by decreasing TRα1 mRNA levels twofold. This change in isoform ratio is accompanied by a decrease in 5′-deiodinase expression, whereas no differences were found in TRβ1 expression. Deletion of the RNA-processing domain of PGC-1α abrogated the effect on the TRα splicing, whereas expression of only the RNA-processing domain favored TRα1 expression. PGC-1α showed a similar effect on the splicing of a TRα minigene containing only the last four exons and introns of the TRα gene. These data suggest that PGC-1α is involved in the RNA processing of TRα transcripts.
New insights on the mechanism(s) of the dominant negative effect of mutant thyroid hormone receptor in generalized resistance to thyroid hormone.
