Oct4, Sox2, and Nanog are key components of a core transcriptional regulatory network that controls the ability of embryonic stem cells to differentiate into all cell types. Here we show that Zfp281, a zinc finger transcription factor, is a key component of the network and that it is required to maintain pluripotency. Zfp281 was shown to directly activate Nanog expression by binding to a site in the promoter in very close proximity to the Oct4 and Sox2 binding sites. We present data showing that Zfp281 physically interacts with Oct4, Sox2, and Nanog. Chromatin immunoprecipitation experiments identified 2,417 genes that are direct targets for regulation by Zfp281, including several transcription factors that are known regulators of pluripotency, such as Oct4, Sox2, and Nanog. Gene expression microarray analysis indicated that some Zfp281 target genes were activated, whereas others were repressed, upon knockdown of Zfp281. The identification of both activation and repression domains within Zfp281 suggests that this transcription factor plays bifunctional roles in regulating gene expression within the network.
Zfp206 (ZNF206 in human) encodes a zinc finger-and SCAN domain-containing protein that is highly expressed in pluripotent ESC. Upon differentiation of human and mouse ESC, Zfp206 expression is quickly repressed. Zfp206 was found to be expressed throughout embryogenesis but absent in adult tissues except testis. We have identified a role for Zfp206 in controlling ESC differentiation. ESC engineered to overexpress Zfp206 were found to be resistant to differentiation induced by retinoic acid. In addition, ESC with knocked-down expression of Zfp206 were more sensitive to differentiation by retinoic acid treatment. We found that Zfp206 was able to enhance expression from its own promoter and also activate transcription of the Oct4 and Nanog promoters. Our results show that Zfp206 is an embryonic transcription factor that plays a role in regulating pluripotency of embryonic stem cells.
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