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Abstract
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.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Acknowledgments
We thank Michelle Mathews at the UNC Anatomic Pathology Translational Core Laboratory (APTCL) for expert technical assistance, and to Irina Tikhonova at the Yale Center for Genome Analysis (YCGA) for the assistance and analysis of DNA methylation. The UNC APTCL is supported, in part, by grants from the UNC University Cancer Research Fund (UCRF). This work was supported by National Cancer Institute/National Institutes of Health grants 1R01CA125273, 3R01CA125273–03S1, the Department of Defense (DoD) W81XWH-10–1-0265 (P.B.), the Chilean grants BMRC CTU06 (G.O.) and FONDECYT 1120292 (M.C.), the Chilean government science and technology grant CONICYT 21100327 (R.E.), and the Researcher Professor Grant by the Fulbright García-Robles Foundation (COMEXUS) (K.J.M.).