Maf1 and repression of RNA polymerase III-mediated transcription drives adipocyte differentiation

RNA polymerase (pol) III transcribes a variety of small untranslated RNAs that are involved in essential cellular processes that include transcription, RNA processing, and translation. RNA pol III and its components are altered in various human developmental disorders, yet their roles in cell fate determination and development are poorly understood. Here we demonstrate that Maf1, a transcriptional repressor, promotes induction of mouse embryonic stem cells into mesoderm and their terminal differentiation into adipocytes. Reduced Maf1 expression in preadipocytes impairs adipogenesis while ectopic Maf1 expression in Maf1-/- deficient cells enhances differentiation. RNA pol III repression by either chemical inhibition or knockdown of Brf1, promotes adipogenesis. Altered RNA pol III-dependent transcription produces select changes in RNA pol II-derived transcripts with a significant enrichment of adipogenic gene signatures. Furthermore, RNA pol III-mediated transcription positively regulates long non-coding RNA H19 and Wnt6 expression, established adipogenesis inhibitors. Together, these studies reveal an important and unexpected function for RNA pol III-mediated transcription and Maf1 in mesoderm induction and cellular differentiation. Overall design: Gene expression profiling by RNA-seq at two time points (day 0: before differentiation, day 2: two days after differentiation) with knockdown by shRNA of Maf1 and Brf1, respectively, and RNA Pol III inhibitor, ML-60218, treatment compare to the control (empty shRNA vector) in 3T3-L1 cells.

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Chen CY, Lanz RB, Walkey CJ, Chang WH, Lu W, Johnson DL