Ly-1 Antibody Reactive Clone Is an Important Nucleolar Protein for Control of Self-Renewal and Differentiation in Embryonic Stem Cells
Ly-1 Antibody Reactive Clone Is an Important Nucleolar Protein for Control of Self-Renewal and Differentiation in Embryonic Stem Cells
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Ly-1 抗体反应克隆是控制胚胎干细胞自我更新和分化的重要核仁蛋白
DOI：
10.1002/stem.55
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发表时间：
2009-01-01
期刊：
影响因子：
5.2
通讯作者：
Jin, Ying
中科院分区：
文献类型：
--
作者：
Li, Hui;Wang, Beibei;Jin, Ying
胚胎干细胞(ESCs)具有自我更新和分化为生物体所有细胞类型的能力。了解这些特性是如何控制的，对于它们的衍生物在临床环境中的潜在用途和分化的体细胞的重新编程是至关重要的。虽然转录因子，如Oct4，Sox2和Nanog，被认为是核心调控电路的一部分，但越来越多的证据表明，还有其他因素存在，并有助于控制ESC的自我更新和分化。在这里，我们报道了Ly-1抗体反应性克隆(LYAR)，一种在未分化的ESCs中高度表达的锌指核仁蛋白，在维持ESCs的特性方面发挥了关键作用。其下调显著降低了ESC的生长速度，增加了ESC的凋亡率。此外，LYAR在ESCs中的表达减少削弱了其分化能力，无法在分化时迅速沉默多潜能标记物和激活分化基因。从机制上讲，LYAR与另一种核仁蛋白核仁形成复合体，并阻止其自我切割，在未分化的ESCs中维持核仁蛋白的正常稳定水平。有趣的是，核仁素的下调不利于ESCs的生长，并增加了凋亡率，这与LYAR的下调类似。因此，我们的数据强调了除了Oct4和Nanog之外的其他基因对于胚胎干细胞的自我更新和分化是唯一需要的，并证明了LYAR功能控制核仁蛋白的稳定性，而核仁蛋白对维持胚胎干细胞的自我更新是必不可少的。干细胞2009；27：1244-1254
Embryonic stem cells (ESCs) possess the capacity to self-renew and differentiate into all cell types of an organism. It is essential to understand how these properties are controlled for the potential usage of their derivatives in clinical settings and reprogramming of differentiated somatic cells. Although transcriptional factors, such as Oct4, Sox2, and Nanog, have been considered as a part of the core regulatory circuitry, a growing body of evidence suggests that additional factors exist and contribute to the control of ESC self-renewal and differentiation. Here, we report that Ly-1 antibody reactive clone (LYAR), a zinc finger nucleolar protein highly expressed in undifferentiated ESCs, plays a critical role in maintaining ESC identity. Its downregulation significantly reduces the rate of ESC growth and increases their apoptosis. Moreover, reduced expression of LYAR in ESCs impairs their differentiation capacity, failing to rapidly silence pluripotency markers and to activate differentiation genes upon differentiation. Mechanistically, LYAR forms a complex with another nucleolar protein, nucleolin, and prevents its self-cleavage, maintaining a normal steady-state level of nucleolin protein in undifferentiated ESCs. Interestingly, the downregulation of nucleolin is detrimental to the growth of ESCs and increases the rate of apoptosis, similarly to the knockdown of LYAR. Thus, our data emphasize the fact that other genes besides Oct4 and Nanog are uniquely required for ESC self-renewal and differentiation and demonstrate that LYAR functions to control the stability of nucleolin protein, which in turn is essential for maintaining the self-renewal of ESCs. STEM CELLS 2009;27:1244-1254