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

Abstract

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/EBPbeta and C/EBPdelta protein expression without affecting mRNA levels in the early phase of differentiation. However, ectopic expression of C/EBPbeta and C/EBPdelta did not rescue differentiation. Further analysis demonstrated that JMJD6 was associated with the Ppargamma2 and Cebpalpha 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, Ppargamma2 and Cebpalpha expression, and adipogenic differentiation, yet had no effect on C/EBPbeta and C/EBPdelta expression or chromatin binding. These results indicate dual roles for JMJD6 in promoting adipogenic gene expression program by post-transcriptional regulation of C/EBPbeta and C/EBPdelta and direct transcriptional activation of Ppargamma2 and Cebpalpha during adipocyte differentiation.