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

The coordinated and sequential actions of lineage-specific transcription factors and epigenetic regulators are essential for the initiation and maintenance of cellular differentiation. We here report KDM4D histone demethylase as a key regulator of adipogenesis in C3H10T1/2 mesenchymal stem cells. The depletion of KDM4D results in impaired differentiation, which can be rescued by exogenous KDM4D, PPAR gamma, and C/EBP alpha, but not by C/EBP ss. In addition, KDM4D interacts physically and functionally with both NFIB and MLL1 complex to regulate C/EBP alpha and PPAR gamma expression upon adipogenic hormonal induction. Although KDM4D is dispensable for the binding of both NFIB and MLL1 complex to the target promoters, the demethylation of tri-methylated H3K9 by KDM4D is required for NFIB and MLL1 complex to deposit tri-methylated H3K4 and activate PPAR gamma and C/EBP alpha expression. Taken together, our data provide a molecular framework for lineage-specific transcription factor and histone modifiers to cooperate in adipogenic differentiation, in which KDM4D removes repressive histone marks at genes with a bivalent chromatin domain and allows NFIB and MLL1 complex to promote the expression of key adipogenic regulators.