PGC-1alpha regulates the isoform mRNA ratio of the alternatively spliced thyroid hormone receptor alpha transcript.
Transcripts derived from the thyroid hormone receptor alpha (TRalpha) gene are alternatively spliced resulting in a functional receptor TRalpha1 and a non-T3-binding variant TRalpha2 that can exert a dominant negative effect on the transactivation functions of other TRs. There is evidence that the ratio of TRalpha isoform transcripts can be modulated and here, we investigate whether the PPARgamma co-activator alpha (PGC-1alpha) has an effect on this splicing process. PGC-1alpha was discovered not only as a transcriptional co-activator, but also has certain motifs characteristic of splicing factors. We demonstrate that PGC-1alpha alters the ratio of endogenously expressed TRalpha isoform transcripts in HepG2 cells, by decreasing TRalpha1 mRNA levels twofold. This change in isoform ratio is accompanied by a decrease in 5'-deiodinase expression, whereas no differences were found in TRbeta1 expression. Deletion of the RNA-processing domain of PGC-1alpha abrogated the effect on the TRalpha splicing, whereas expression of only the RNA-processing domain favored TRalpha1 expression. PGC-1alpha showed a similar effect on the splicing of a TRalpha minigene containing only the last four exons and introns of the TRalpha gene. These data suggest that PGC-1alpha is involved in the RNA processing of TRalpha transcripts.
Thijssen-Timmer
D C
DC
Department of Endocrinology and Metabolism, Academic Medical Centre, F5-171, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Schiphorst
M Platvoet-Ter
MP
Kwakkel
J
J
Emter
R
R
Kralli
A
A
Wiersinga
W M
WM
Bakker
O
O
D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D050505:Mutant Proteins / Q000502:physiology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020033:Protein Isoforms / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D037021:Thyroid Hormone Receptors alpha / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014284:Triiodothyronine / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D006360:Heat-Shock Proteins; D050505:Mutant Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020033:Protein Isoforms; D012333:RNA, Messenger; D037021:Thyroid Hormone Receptors alpha; D014157:Transcription Factors; D014284:Triiodothyronine