Splicing factor ASF/SF2 and transcription factor PPAR-γ 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-γ. We found that ASF/SF2 activates formation of long-form UCP3 (UCP3L) by inhibiting a cleavage and polyadenylation signal (AATAAA) located in its final intron that prematurely terminates message elongation. PPAR-γ 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 UCP3L, whereas loss of ASF/SF2 decreases production of both UCP3L and short-form UCP3 (UCP3S). We suggest that the relative abundance of ASF/SF2 and PPAR-γ determines the ratio of UCP3 isoforms.