Antagonism between the Master Regulators of Differentiation Ensures the Discreteness and Robustness of Cell Fates

The discreteness of cell fates is an inherent and fundamental feature of multicellular organisms. Here we show that cross-antagonistic mechanisms of actions of MyoD and PPARg, which are the master regulators of muscle and adipose differentiation, respectively, confer the robustness to the integrity of cell differentiation. Simultaneous expression of MyoD and PPARg in mesenchymal stem/stromal cells led to the generation of a mixture of multinucleated myotubes and lipid-filled adipocytes. Interestingly, hybrid cells, i.e., lipid-filled myotubes, were not generated, suggesting that these differentiation programs are mutually exclusive. Mechanistically, while exogenously expressed MyoD was rapidly degraded in adipocytes through ubiquitin-proteasome pathways, exogenously expressed PPARg was not down-regulated in myotubes. In PPARg-expressing myotubes, PPARg-dependent histone hyperacetylation was inhibited in a subset of adipogenic gene loci, including that of C/EBPa, an essential effector of PPARg. Thus, the cross-repressive interactions between MyoD- and PPARg-induced differentiation programs ensure the discrete cell fate decisions.

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Sunadome K, Suzuki T, Usui M, Ashida Y, Nishida E