title: Breaking through an epigenetic wall: re-activation of Oct4 by KRAB-containing designer zinc finger transcription factors.
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.
authors: Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors: Karla
authors: K
authors: Juárez-Moreno
authors: Rafaela
authors: R
authors: Erices
authors: Adriana S
authors: AS
authors: Beltran
authors: Sabine
authors: S
authors: Stolzenburg
authors: Mauricio
authors: M
authors: Cuello-Fredes
authors: Gareth I
authors: GI
authors: Owen
authors: Haili
authors: H
authors: Qian
authors: Pilar
authors: P
authors: Blancafort
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics; D045744:Cell Line, Tumor; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D050814:Octamer Transcription Factor-3 / Q000235:genetics* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D011994:Recombinant Proteins; D012097:Repressor Proteins; C422407:ZNF350 protein, human
keywords: DNA methylation; KRAB domain; Oct4; Zinc Finger Proteins; artificial transcription factors; breast cancer; epigenetics; serous epithelial ovarian cancer