Splicing factor ASF/SF2 and transcription factor PPAR-gamma cooperate to directly regulate transcription of uncoupling protein-3.
The different isoforms of the uncoupling protein-3 (UCP3) are expressed in skeletal muscle and are up-regulated by splicing factors. Here, we report that UCP3 alternative splicing (alternative polyadenylation) is regulated by cooperation between the splicing factor ASF/SF2 and the transcription factor PPAR-gamma. We found that ASF/SF2 activates formation of long-form UCP3 (UCP3(L)) by inhibiting a cleavage and polyadenylation signal (AATAAA) located in its final intron that prematurely terminates message elongation. PPAR-gamma activates this process by directly interacting with ASF/SF2, providing the first example of a direct link between a transcription factor and alternative splicing. Activation of ASF/SF2 promotes formation of UCP3(L), whereas loss of ASF/SF2 decreases production of both UCP3(L) and short-form UCP3 (UCP3(S)). We suggest that the relative abundance of ASF/SF2 and PPAR-gamma determines the ratio of UCP3 isoforms.
Kim
Dong-Joon
DJ
Center for Genome Science, National Institute of Health in Korea, Eunpyung-Gu, Seoul, Republic of Korea.
Oh
Bermseok
B
Kim
Young-Youl
YY
D017398:Alternative Splicing; D002460:Cell Line; D005091:Exons; D006801:Humans; D007438:Introns; D007473:Ion Channels / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics; D016601:RNA-Binding Proteins; D012091:Repetitive Sequences, Nucleic Acid; D000068103:Serine-Arginine Splicing Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D000071247:Uncoupling Protein 3
D007473:Ion Channels; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; D047495:PPAR gamma; D020033:Protein Isoforms; D016601:RNA-Binding Proteins; C000604392:UCP3 protein, human; D000071247:Uncoupling Protein 3; D000068103:Serine-Arginine Splicing Factors