The FBXL10/KDM2B Scaffolding Protein Associates with Novel Polycomb Repressive Complex-1 to Regulate Adipogenesis

Abstract Polycomb repressive complex 1 (PRC1) plays an essential role in the epigenetic repression of gene expression during development and cellular differentiation via multiple effector mechanisms including ubiquitination of H2A and chromatin compaction. However, whether it regulates the step-wise progression of adipogenesis is unknown. Here we show that FBXL10/KDM2B is an anti-adipogenic factor that is up-regulated during the early phase of 3T3-L1 preadipocyte differentiation and in adipose tissue in a diet induced model of obesity. Interestingly, inhibition of adipogenesis does not require the JmjC demethylase domain of FBXL10 but it does require the F-box and leucine rich repeat (LRRs) domains which we show recruit a non-canonical polycomb repressive complex 1 (PRC1) containing RING1B, SKP1, PCGF1 and BCOR. Knockdown of either RING1B or SKP1 prevented FBXL10 mediated repression of 3T3-L1 preadipocyte differentiation indicating that PRC1 formation mediates the inhibitory effect of FBXL10 on adipogenesis. Using ChIP-seq we show that FBXL10 recruits RING1B to key specific genomic loci surrounding the key cell-cycle and adipogenic genes Cdk1, Uhrf1, Pparg1 and Pparg2 to repress adipogenesis. These results suggest that FBXL10 represses adipogenesis through targeting a non-canonical PRC1 complex to repress key genes (e.g. Pparg) that control conversion of pluripotent cells into the adipogenic lineage.