ORIGINAL ARTICLE

Cell Research (2008): 216-223
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Adipogenesis licensing and execution are disparately linked to cell proliferation

Wei Guo^1,2,*, Kun-Ming Zhang^1,2,*, Kang Tu¹, Yi-Xue Li¹, Li Zhu¹, Hua-Sheng Xiao^1,3, Ying Yang^1,2 and Jia-Rui Wu^1,2,4

Correspondence: Jia-Rui Wu, Tel: +86-021-54921128; Fax: +86-021-54920787 E-mail: wujr@sibs.ac.cn *These authors contributed equally to this work.

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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.

Cell Research (2009) 19:216-223. doi: 10.1038/cr.2008.319; published online 9 December 2008

Keywords: adipogenesis, proliferation, contact inhibition, DNA methylation, C/EBPα