Blizard Institute, Barts & The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
Stem Cells. 2013 Jan;31(1):190-202. doi: 10.1002/stem.1274.
Polycomb group proteins are essential regulators of stem cell function during embryonic development and in adult tissue homeostasis. Bmi1, a key component of the Polycomb Repressive Complex 1, is highly expressed in undifferentiated neural stem cells (NSC) as well as in several human cancers including high-grade gliomas--highly aggressive brain tumors. Using a conditional gene activation approach in mice, we show that overexpression of Bmi1 induces repressive epigenetic regulation of the promoter of Survivin, a well-characterized antiapoptotic protein. This phenomenon is cell type-specific and it leads to apoptotic death of progenitor cells exclusively upon commitment toward a neuronal fate. Moreover, we show that this is triggered by increased oxidative stress-induced DNA damage. In contrast, undifferentiated NSC as well as glioma-initiating cells display an open chromatin configuration at the Survivin promoter and do not undergo apoptotic death. These findings raise the possibility that normal and neoplastic stem cells depend on the same mechanism for surviving the hyperproliferative state induced by increased Bmi1 expression.
多梳蛋白是胚胎发育过程中干细胞功能和成人组织稳态的重要调节因子。Bmi1 是多梳抑制复合物 1 的关键组成部分，在未分化的神经干细胞（NSC）以及包括高级别神经胶质瘤在内的几种人类癌症中高度表达，高级别神经胶质瘤是一种高度侵袭性的脑肿瘤。我们通过在小鼠中使用条件基因激活方法表明，Bmi1 的过表达诱导了存活素启动子的抑制性表观遗传调控，存活素是一种特征明确的抗凋亡蛋白。这种现象是细胞类型特异性的，它仅在祖细胞向神经元命运分化时导致祖细胞的凋亡死亡。此外，我们表明这是由氧化应激诱导的 DNA 损伤增加引发的。相比之下，未分化的 NSC 以及神经胶质瘤起始细胞在存活素启动子处显示出开放的染色质构型，并且不会发生凋亡死亡。这些发现提出了这样一种可能性，即正常和肿瘤干细胞依赖于相同的机制来存活由 Bmi1 表达增加引起的过度增殖状态。
