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

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-β （TGF-β） in lung adenocarcinoma cells, the mechanism through which...

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Published in:Cell research 2014-08, Vol.24 (8), p.994-1008
Main Authors: Isogaya, Kazunobu, Koinuma, Daizo, Tsutsumi, Shuichi, Saito, Roy-Akira, Miyazawa, Keiji, Aburatani, Hiroyuki, Miyazono, Kohei
Format: Article
Language:English
Subjects:
Cell Line, Tumor
Chromatin - metabolism
Chromatin Immunoprecipitation
DNA-Binding Proteins - antagonists & inhibitors
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Gene Expression - drug effects
Humans
Original
Protein Binding
RNA Interference
RNA, Small Interfering - metabolism
Signal Transduction - drug effects
Smad3
Smad3 Protein - metabolism
Smad4
Smad4 Protein - antagonists & inhibitors
Smad4 Protein - genetics
Smad4 Protein - metabolism
Transcription Factors
Transforming Growth Factor beta - pharmacology
依赖性
基因表达
染色质免疫沉淀
肺上皮细胞
蛋白相互作用
转化生长因子
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cited_by cdi_FETCH-LOGICAL-c565t-3b0ccf5b2a189368f6a395d1f386aa9496d15be5959af6a7d241374f23bc38183
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creator Isogaya, Kazunobu
Koinuma, Daizo
Tsutsumi, Shuichi
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Miyazawa, Keiji
Aburatani, Hiroyuki
Miyazono, Kohei
description 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-β （TGF-β） in lung adenocarcinoma cells, the mechanism through which TTF-1 inhibits the functions of TGF-β 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-β 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-β-Smad signaling by TTF-1.
doi_str_mv 10.1038/cr.2014.97
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Although TTF-1 inhibits the epithelial-to-mesenchymal transition induced by transforming growth factor-β （TGF-β） in lung adenocarcinoma cells, the mechanism through which TTF-1 inhibits the functions of TGF-β 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-β 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-β-Smad signaling by TTF-1.</notes><notes>31-1568/Q</notes><notes>ChlP-seq; NKX2-1; Smad3; Smad4; TTF- 1; TGF-β</notes><notes>ObjectType-Article-2</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-1</notes><notes>content type line 23</notes><abstract>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-β （TGF-β） in lung adenocarcinoma cells, the mechanism through which TTF-1 inhibits the functions of TGF-β 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-β 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-β-Smad signaling by TTF-1.</abstract><cop>England</cop><pub>Nature Publishing Group</pub><pmid>25060702</pmid><doi>10.1038/cr.2014.97</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record>
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subjects Cell Line, Tumor
Chromatin - metabolism
Chromatin Immunoprecipitation
DNA-Binding Proteins - antagonists & inhibitors
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Gene Expression - drug effects
Humans
Original
Protein Binding
RNA Interference
RNA, Small Interfering - metabolism
Signal Transduction - drug effects
Smad3
Smad3 Protein - metabolism
Smad4
Smad4 Protein - antagonists & inhibitors
Smad4 Protein - genetics
Smad4 Protein - metabolism
Transcription Factors
Transforming Growth Factor beta - pharmacology
依赖性
基因表达
染色质免疫沉淀
肺上皮细胞
蛋白相互作用
转化生长因子
title A Smad3 and TTF-1/NKX2-1 complex regulates Smad4-independent gene expression
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