The transcription factor Jun dimerization protein 2 (JDP2) binds directly to histones and inhibits the p300-mediated acetylation of core histones in vitro and of reconstituted nucleosomes that contain JDP2-recognition sequences. The region of JDP2 that encompasses both its histone-binding domain and its DNA-binding region is essential for the inhibition of histone acetylation by histone acetyltransferases (HATs). Moreover, assays of nucleosome assembly in vitro demonstrate that JDP2 also has histone chaperone activity. JDP2 plays a key role as a repressor of cell differentiation by regulating the expression of genes with an AP-1 site via inhibition of histone acetylation and/or the assembly and disassembly of nucleosomes. Here, we summarize the novel function of inhibition of methylation of histone H3 K27 via the polycomb repressive complexes (PRC-1 and PRC-2), which are responsible for histone methylation and bind efficiently to the promoter to repress the expression of the p16^Ink4a gene. As a result, JDP2-deficient cells become resistant to replicative senescence via epigenetic regulation of the expression of the p16^Ink4a gene.