A Smad3 and TTF-1/NKX2-1 complex regulates Smad4-independent gene expression

作者：Isogaya Kazunobu; Koinuma Daizo; Tsutsumi Shuichi; Saito Roy Akira; Miyazawa Keiji; Aburatani Hiroyuki; Miyazono Kohei^*

来源：Cell Research, 2014, 24(8): 994-1008.

DOI：10.1038/cr.2014.97

• ChIP-seq
• NKX2-1
• Smad3
• Smad4
• TTF-1
• TGF-beta

Thyroid transcription factor-1 (TTF-1, also known as NKX2-1) is a tissue-specific transcription factor in lung epithelial cells. Although TTF-1 inhibits the epithelial-to-mesenchymal transition induced by transforming growth factor-beta (TGF-beta) in lung adenocarcinoma cells, the mechanism through which TTF-1 inhibits the functions of TGF-beta is unknown. Here we show that TTF-1 disrupts the nuclear Smad3-Smad4 complex without affecting the nuclear localization of phospho-Smad3. Genome-wide analysis by chromatin immunoprecipitation followed by sequencing revealed that TTF-1 colocalizes with Smad3 on chromatin and alters Smad3-binding patterns throughout the genome, while TTF-1 generally inhibits Smad4 binding to chromatin. Moreover, Smad3 binds to chromatin together with TTF-1, but not with Smad4, at some Smad3-binding regions when TGF-beta signaling is absent, and knockdown of Smad4 expression does not attenuate Smad3 binding in these regions. Thus, TTF-1 may compete with Smad4 for interaction with Smad3, and in the presence of TTF-1, Smad3 regulates the transcription of certain genes independently of Smad4. These findings provide a new model of regulation of TGF-beta-Smad signaling by TTF-1.

• 出版日期2014-8