Regulation of adipogenesis by histone methyltransferases.

Epigenetic regulation is a critical component of lineage determination. Adipogenesis is the process through which uncommitted stem cells or adipogenic precursor cells differentiate into adipocytes, the most abundant cell type of the adipose tissue. Studies examining chromatin modification during adipogenesis have provided further understanding of the molecular blueprint that controls the onset of adipogenic differentiation. Unlike histone acetylation, histone methylation has context dependent effects on the activity of a transcribed region of DNA, with individual or combined marks on different histone residues providing distinct signals for gene expression. Over half of the 42 histone methyltransferases identified in mammalian cells have been investigated in their role during adipogenesis, but across the large body of literature available, there is a lack of clarity over potential correlations or emerging patterns among the different players. In this review, we will summarize important findings from studies published in the past 15 years that have investigated the role of histone methyltransferases during adipogenesis, including both protein arginine methyltransferases (PRMTs) and lysine methyltransferases (KMTs). We further reveal that PRMT1/4/5, H3K4 KMTs (MLL1, MLL3, MLL4, SMYD2 and SET7/9) and H3K27 KMTs (EZH2) all play positive roles during adipogenesis, while PRMT6/7 and H3K9 KMTs (G9a, SUV39H1, SUV39H2, and SETDB1) play negative roles during adipogenesis.

Downregulation of SUV39H1 and CITED2 Exerts Additive Effect on Promoting Adipogenic Commitment of Human Mesenchymal Stem Cells.

Human adipogenesis is the process through which uncommitted human mesenchymal stem cells (hMSCs) differentiate into adipocytes. Through a siRNA-based high-throughput screen that identifies adipogenic regulators whose expression knockdown leads to enhanced adipogenic differentiation of hMSCs, two new regulators, SUV39H1, a histone methyltransferase that catalyzes H3K9Me3, and CITED2, a CBP/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 were uncovered. Both SUV39H1 and CITED2 are normally downregulated during adipogenic differentiation of hMSCs. Further expression knockdown induced by siSUV39H1 or siCITED2 at the adipogenic initiation stage significantly enhanced adipogenic differentiation of hMSCs as compared with siControl treatment, with siSUV39H1 acting by both accelerating fat accumulation in individual adipocytes and increasing the total number of committed adipocytes, whereas siCITED2 acting predominantly by increasing the total number of committed adipocytes. In addition, both siSUV39H1 and siCITED2 were able to redirect hMSCs to undergo adipogenic differentiation in the presence of osteogenic inducing media, which normally only induces osteogenic differentiation of hMSCs in the absence of siSUV39H1 or siCITED2. Interestingly, simultaneous knockdown of both SUV39H1 and CITED2 resulted in even greater levels of adipogenic differentiation of hMSCs and expression of CEBPα and PPARγ, two master regulators of adipogenesis, as compared with those elicited by single gene knockdown. Furthermore, the effects of co-knockdown were equivalent to the additive effect of individual gene knockdown. Taken together, this study demonstrates that SUV39H1 and CITED2 are both negative regulators of human adipogenesis, and downregulation of both genes exerts an additive effect on promoting adipogenic differentiation of hMSCs through augmented commitment.