Transcriptional and post-transcriptional control of adipocyte differentiation by Jumonji domain-containing protein 6

Jumonji domain-containing protein 6 (JMJD6) is a nuclear protein involved in histone modification, transcription and RNA processing. Although JMJD6 is crucial for tissue development, the link between its molecular functions and its roles in any given differentiation process is unknown. We report that JMJD6 is required for adipogenic gene expression and differentiation in a manner independent of Jumonji C domain catalytic activity. JMJD6 knockdown led to a reduction of C/EBPβ and C/EBPδ protein expression without affecting mRNA levels in the early phase of differentiation. However, ectopic expression of C/EBPβ and C/EBPδ did not rescue differentiation. Further analysis demonstrated that JMJD6 was associated with the Pparγ2 and Cebpα loci and putative enhancers. JMJD6 was previously found associated with bromodomain and extra-terminal domain (BET) proteins, which can be targeted by the bromodomain inhibitor JQ1. JQ1 treatment prevented chromatin binding of JMJD6, Pparγ2 and Cebpα expression, and adipogenic differentiation, yet had no effect on C/EBPβ and C/EBPδ expression or chromatin binding. These results indicate dual roles for JMJD6 in promoting adipogenic gene expression program by post-transcriptional regulation of C/EBPβ and C/EBPδ and direct transcriptional activation of Pparγ2 and Cebpα during adipocyte differentiation.