The highly expressed lipid buffer FABP4 enforces adipocyte cell identity by driving the initial cell differentiation process
The highly expressed lipid buffer FABP4 enforces adipocyte cell identity by driving the initial cell differentiation process
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高表达的脂质缓冲液 FABP4 通过驱动初始细胞分化过程来增强脂肪细胞的细胞特性
DOI：
10.1101/2020.01.03.894493
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通讯作者：
Teruel M.
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作者：
Bahrami-Nejad Z;Chen T;Tholen S;Teruel M.
考虑到细胞所处的信号环境波动，以及关键的转录因子通常不是分化过程中独有的，祖细胞如何才能获得不同的分化细胞身份是一个具有挑战性的问题。在这里，我们测试了一种假设，即独特的分化细胞身份可以产生于分化状态的核心成分，同时也是驱动分化的信号蛋白。在脂肪细胞分化系统中使用活的单细胞成像，我们发现前体脂肪细胞(前脂肪细胞)只有在上调FABP4之后才能致力于终末分化，FABP4是一种在成熟脂肪细胞中高度丰富的脂质缓冲区。在诱导小鼠前脂肪细胞成脂后，我们发现，在长时间的延迟之后，细胞首先突然开始在CEBPA和PPARG之间进行正反馈，然后在第二次延迟后，在FABP4和PPARG之间进行正反馈。这些连续的正反馈都需要参与，以推动PPARG水平超过不可逆转分化的阈值。在承诺前的最后一步，PPARG在转录上增加FABP4的表达，而脂肪酸负载的FABP4则增加PPARG的活性。综上所述，我们的研究提出了一种稳健的细胞同一性的控制原则，即分化状态的核心成分也促进了与其自身祖细胞状态的分化。
How progenitor cells can attain a distinct differentiated cell identity is a challenging problem given the fluctuating signaling environment in which cells exist and that critical transcription factors are often not unique to a differentiation process. Here, we test the hypothesis that a unique differentiated cell identity can result from a core component of the differentiated state doubling up as a signaling protein that also drives differentiation. Using live single-cell imaging in the adipocyte differentiation system, we show that progenitor fat cells (preadipocytes) can only commit to terminally differentiate after up-regulating FABP4, a lipid buffer that is highly enriched in mature adipocytes. Upon induction of adipogenesis in mouse preadipocyte cells, we show that after a long delay, cells first abruptly start to engage a positive feedback between CEBPA and PPARG before then engaging, after a second delay, a positive feedback between FABP4 and PPARG. These sequential positive feedbacks both need to engage in order to drive PPARG levels past the threshold for irreversible differentiation. In the last step before commitment, PPARG transcriptionally increases FABP4 expression while fatty acid-loaded FABP4 increases PPARG activity. Together, our study suggests a control principle for robust cell identity whereby a core component of the differentiated state also promotes differentiation from its own progenitor state.