NANOG Is a Direct Target of TGFβ/Activin-Mediated SMAD Signaling in Human ESCs

Ren He Xu, Tori L. Sampsell-Barron, Feng Gu, Sierra Root, Ruthann M. Peck, Guangjin Pan, Junying Yu, Jessica Antosiewicz-Bourget, Shulan Tian, Ron Stewart, James A. Thomson

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)196-206
Number of pages11
JournalCell Stem Cell
Issue number2
StatePublished - Aug 7 2008



ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology


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