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/ EBP beta and C/ EBP delta protein expression without affectingmRNA levels in the early phase of differentiation. However, ectopic expression of C/ EBP beta and C/ EBP delta did not rescue differentiation. Further analysis demonstrated that JMJD6 was associated with the Ppar.2 and Cebp alpha 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, Ppar.2 and Cebpa expression, and adipogenic differentiation, yet had no effect on C/ EBP beta and C/ EBP delta expression or chromatin binding. These results indicate dual roles for JMJD6 in promoting adipogenic gene expression program by post-transcriptional regulation of C/ EBP beta and C/ EBP delta and direct transcriptional activation of Ppar.2 and Cebpa during adipocyte differentiation.