@article{dab091482b6c4ad4a8f1ecc63a577cb3,
title = "NANOG Is a Direct Target of TGFβ/Activin-Mediated SMAD Signaling in Human ESCs",
abstract = "Self-renewal of human embryonic stem cells (ESCs) is promoted by FGF and TGFβ/Activin signaling, and differentiation is promoted by BMP signaling, but how these signals regulate genes critical to the maintenance of pluripotency has been unclear. Using a defined medium, we show here that both TGFβ and FGF signals synergize to inhibit BMP signaling; sustain expression of pluripotency-associated genes such as NANOG, OCT4, and SOX2; and promote long-term undifferentiated proliferation of human ESCs. We also show that both TGFβ- and BMP-responsive SMADs can bind with the NANOG proximal promoter. NANOG promoter activity is enhanced by TGFβ/Activin and FGF signaling and is decreased by BMP signaling. Mutation of putative SMAD binding elements reduces NANOG promoter activity to basal levels and makes NANOG unresponsive to BMP and TGFβ signaling. These results suggest that direct binding of TGFβ/Activin-responsive SMADs to the NANOG promoter plays an essential role in sustaining human ESC self-renewal.",
keywords = "STEMCELL",
author = "Xu, {Ren He} and Sampsell-Barron, {Tori L.} and Feng Gu and Sierra Root and Peck, {Ruthann M.} and Guangjin Pan and Junying Yu and Jessica Antosiewicz-Bourget and Shulan Tian and Ron Stewart and Thomson, {James A.}",
note = "Funding Information: We thank Tenneille Ludwig and Jenny Frane for providing TeSR1 media; Marian Piekarczyk, Leann Crandall, and Tiwanna Compton for laboratory support; and Deborah Faupel for editing the manuscript. We also thank Gudrun Jonsdottir and Karen Heidarsdottir from the WiCell Research Institute in Iceland for conducting the microarray experiments and Mark Kronenberg for helpful discussion on the EMSA. This work was supported by funding from private donations, National Institutes of Health grants P51 RR000167 and P20 GM069981, the W.M. Keck Foundation to J.A.T., and the Connecticut Stem Cell Research Grants 06SCB14 and 06SCD02 to R.-H.X. The contents in this work are solely the responsibility of the authors and do not necessarily represent the official views of the State of Connecticut. The authors declare competing financial interests. J.A.T. is a cofounder and shareholder of Cellular Dynamics International. ",
year = "2008",
month = aug,
day = "7",
doi = "10.1016/j.stem.2008.07.001",
language = "English (US)",
volume = "3",
pages = "196--206",
journal = "Cell Stem Cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "2",
}