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首页> 外文期刊>Molecular cell >Antagonism between the Master Regulators of Differentiation Ensures the Discreteness and Robustness of Cell Fates
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Antagonism between the Master Regulators of Differentiation Ensures the Discreteness and Robustness of Cell Fates

机译:分化的主要调节剂之间的拮抗作用确保细胞命运的离散性和鲁棒性

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摘要

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 ofcell 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.
机译:细胞命运的离散性是多细胞生物的固有和基本特征。在这里我们表明,MyoD和PPARγ的交叉拮抗作用机制分别是肌肉和脂肪分化的主要调节剂,赋予细胞分化的完整性鲁棒性。 MyoD和PPARγ在间充质干细胞/基质细胞中的同时表达导致多核肌管和脂质填充的脂肪细胞的混合物的产生。有趣的是,没有产生杂交细胞(即充满脂质的肌管),表明这些分化程序是互斥的。从机制上讲,尽管外源表达的MyoD通过泛素-蛋白酶体途径在脂肪细胞中迅速降解,但外源表达的PPARγ在肌管中并未下调。在表达PPARγ的肌管中,PPARγ依赖的组蛋白高乙酰化在部分成脂基因位点(包括C /EBPα,PPARγ的重要效应子)中被抑制。因此,MyoD和PPARγ诱导的分化程序之间的交叉抑制相互作用确保了离散的细胞命运决定。

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