Shortening of the Zfp143 3'UTR by alternative polyadenylation alters ZFP36L1-mediated regulation and promotes adipogenesis.

Understanding the molecular mechanisms governing adipogenesis is essential for elucidating adipose tissue development and metabolic disorders. Alternative polyadenylation (APA) of the 3' untranslated region (3'UTR) has emerged as an important regulatory layer in adipogenesis; however, the functional significance of APA-induced 3'UTR shortening in individual genes remains to be elucidated. This study aimed to investigate the roles and mechanisms of APA-generated zinc-finger protein 143 (Zfp143) isoforms in adipogenesis. The expression pattern of Zfp143 during adipogenesis was characterized, and functional analyses revealed the involvement of Zfp143 in adipogenic differentiation. Using 3'RACE, two Zfp143 isoforms with long and short 3'UTRs were identified. To evaluate the functional differences between APA-generated isoforms, isoform-specific expression constructs containing the identical Zfp143 coding sequence fused with either the short or long 3'UTR were generated. The short 3'UTR isoform exhibited higher Zfp143 expression levels and stronger adipogenic capacity than the long isoform. Dual-luciferase reporter assays, RNA immunoprecipitation assays, and molecular analyses demonstrated differential post-transcriptional regulation between the two isoforms. Mechanistically, the long 3'UTR isoform was negatively regulated by ZFP36L1 binding to AREs within its 3'UTR, whereas the short isoform escaped ZFP36L1-mediated regulation due to the absence of AREs in its 3'UTR. Collectively, these findings reveal an APA-dependent post-transcriptional regulatory mechanism in which ZFP36L1 differentially regulates Zfp143 3'UTR isoforms, thereby fine-tuning Zfp143 expression and adipogenic differentiation during adipogenesis.