Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Epigenetics. 2013 Feb;8(2):164-76. doi: 10.4161/epi.23503. Epub 2013 Jan 11.
The gene Oct4 encodes a transcription factor critical for the maintenance of pluripotency and self-renewal in embryonic stem cells. In addition, improper re-activation of Oct4 contributes to oncogenic processes. Herein, we describe a novel designer zinc finger protein (ZFP) capable of upregulating the endogenous Oct4 promoter in a panel of breast and ovarian cell lines carrying a silenced gene. In some ovarian tumor lines, the ZFP triggered a strong reactivation of Oct4, with levels of expression comparable with exogenous Oct4 cDNA delivery. Surprisingly, the reactivation of Oct4 required a KRAB domain for effective upregulation of the endogenous gene. While KRAB-containing ZFPs are traditionally described as transcriptional repressors, our results suggest that these proteins could, in certain genomic contexts, function as potent activators and, thus, outline an emerging novel function of KRAB-ZFPs. In addition, we document a novel ZFP that could be used for the epigenetic reprograming of cancer cells.
基因 Oct4 编码一种转录因子，对于维持胚胎干细胞的多能性和自我更新至关重要。此外，Oct4 的不当重新激活有助于致癌过程。在此，我们描述了一种新型的设计锌指蛋白（ZFP），它能够上调一组携带沉默基因的乳腺癌和卵巢细胞系中的内源性 Oct4 启动子。在一些卵巢肿瘤系中，ZFP 引发了 Oct4 的强烈重新激活，表达水平与外源性 Oct4 cDNA 传递相当。令人惊讶的是，Oct4 的重新激活需要 KRAB 结构域才能有效上调内源性基因。虽然含有 KRAB 的 ZFP 通常被描述为转录抑制剂，但我们的结果表明，在某些基因组环境下，这些蛋白可能作为有效的激活剂发挥作用，从而描绘出 KRAB-ZFP 的一个新的新兴功能。此外，我们记录了一种新型的 ZFP，可用于癌细胞的表观遗传重编程。
