Adipogenesis licensing and execution are disparately linked to cell proliferation.
Coordination of cell differentiation and proliferation is a key issue in the development process of multi-cellular organisms and stem cells. Here we provide evidence that the establishment of adipocyte differentiation of 3T3-L1 cells requires two processes: the licensing of an adipogenesis gene-expression program within a particular growth-arrest stage, i.e., the contact-inhibition stage, and then the execution of this program in a cell-cycle-independent manner, by which the licensed progenitors are differentiated into adipocytes in the presence of inducing factors. Our results showed that differentiation licensing of 3T3-L1 cells during the contact-inhibition stage involved epigenetic modifications such as DNA methylation and histone modifications, whereas disturbing these epigenetic modifications by DNA methylation inhibitors or RNAi during the contact-inhibition stage significantly reduced adipogenesis efficiency. More importantly, when these licensed 3T3-L1 cells were re-cultured under non-differentiating conditions or treated only with insulin, this adipogenesis commitment could be maintained from one cell generation to the next, whereby the licensed program could be activated in a cell-cycle-independent manner once these cells were subjected to adipogenesis-inducing conditions. This result suggests that differentiation licensing and differentiation execution can be uncoupled and disparately linked to cell proliferation. Our findings deliver a new concept that cell-fate decision can be subdivided into at least two stages, licensing and execution, which might have different regulatory relationships with cell proliferation. In addition, this new concept may provide a clue for developing new strategies against obesity.
Guo
Wei
W
Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.
Zhang
Kun-Ming
KM
Tu
Kang
K
Li
Yi-Xue
YX
Zhu
Li
L
Xiao
Hua-Sheng
HS
Yang
Ying
Y
Wu
Jia-Rui
JR
D041721:3T3-L1 Cells; D050156:Adipogenesis / Q000502:physiology*; D000818:Animals; D049109:Cell Proliferation; D003260:Contact Inhibition / Q000502:physiology; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D006657:Histones / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D051379:Mice; D034741:RNA, Small Interfering; D013234:Stem Cells / Q000166:cytology
D006657:Histones; D007328:Insulin; D034741:RNA, Small Interfering