As a novel type of mesenchymal stem cell, induced pluripotent stem cell-derived mesenchymal stem cells (iPMSCs) have huge potential for cell therapy. iPMSCs exhibited the typical characteristics of MSCs, whereas the tri-lineage differentiation potential is limited, especially the adipogenic propensity. Here, to reveal the molecular mechanism we carried out the epigenetic comparisons between the iPMSCs and the bone marrow-derived mesenchymal stem cells (BMSCs) and embryonic stem cell-derived mesenchymal stem cells (EMSCs). We found that the iPMSCs was significantly higher than the BMSCs in terms of genome-wide DNA methylation. Meanwhile, the adipogenic gene PPAR gamma promoter region existed hypermethylation. In addition, compared with EMSCs and BMSCs, iPMSCs had significant differences in the histones epigenetic modification of methylation and acetylation, especially high levels of histone 27 lysine trimethylation (H3K27me3). Furthermore, the epigenetic modifiers Decitabine and EPZ6438 effectively upregulated the gene expression of PPAR gamma and promoted the adipogenic differentiation of iPMSCs via chromatin remodeling. Taken together, our findings set new metrics to the applications for improving the efficiency and the therapeutic potential of iPMSCs. (C) 2019 Published by Elsevier Inc.