Histone demethylase KDM4D cooperates with NFIB and MLL1 complex to regulate adipogenic differentiation of C3H10T1/2 mesenchymal stem cells

초록

Coordinated and sequential actions of lineage-specific transcription factors and epigenetic regulators are critical for initiation and maintenance of cellular differentiation. We here report KDM4D histone demethylase as a key regulator of adipogenesis in C3H10T1/2 mesenchymal stem cells. We show that depletion of KDM4D results in impaired differentiation, which can be rescued by exogenous KDM4D, PPARγ and C/EBPα, but not by C/EBP??or inhibition of Wnt signaling. In addition, we found that KDM4D physically and functionally interacts with both NFIB and MLL1 complex to regulate C/EBPα and PPARγ expression upon adipogenic hormonal induction. Moreover, we demonstrate that although KDM4D is dispensable for NFIB/MLL1 complex binding to the target promoters, demethylation of tri-methylated H3-K9 by KDM4D is required for NFIB/MLL1 complex to deposit tri-methylated H3-K4 and activate PPARγ and C/EBPα expression. Together, our data provide a molecular framework for lineage-specific transcription factor and histone modifiers to cooperate in adipogenic differentiation, in which function of KDM4D is to remove repressive histone marks at genes with bivalent chromatin domain and therefore allow NFIB/MLL1 complex to promote expression of key adipogenic regulators.