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 PPARγ, which are the master regulators of muscle and adipose differentiation, respectively, confer robustness to the integrity of cell differentiation. Simultaneous expression of MyoD and PPARγ 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, although exogenously expressed MyoD was rapidly degraded in adipocytes through ubiquitin-proteasome pathways, exogenously expressed PPARγ was not downregulated in myotubes. In PPARγ-expressing myotubes, PPARγ-dependent histone hyperacetylation was inhibited in a subset of adipogenic gene loci, including that of C/EBPα, an essential effector of PPARγ. Thus, the cross-repressive interactions between MyoD- and PPARγ-induced differentiation programs ensure discrete cell-fate decisions.
Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan; JST, CREST, Chiyoda-ku, Tokyo 102-0075, Japan.
Kazunori
K
Sunadome
Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
Toshiyasu
T
Suzuki
Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
Mai
M
Usui
Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
Yuhei
Y
Ashida
Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan; JST, CREST, Chiyoda-ku, Tokyo 102-0075, Japan. Electronic address: nishida@lif.kyoto-u.ac.jp.
Eisuke
E
Nishida
D000107:Acetylation; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D057809:HEK293 Cells; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D017570:MyoD Protein / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D059748:Proteolysis; D061785:Transcription Initiation, Genetic
D022762:CCAAT-Enhancer-Binding Proteins; C530718:CEBPA protein, mouse; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D047495:PPAR gamma