Yin Yang 1(YY1) synergizes with Smad7 to inhibit TGF-β signaling in the nucleus

As a prototype of the TGF-β superfamily cytokines, TGF-β is well known for its diverse roles in embryogenesis and adult tis- sue homeostasis. TGF-β evokes cellular responses by signaling mainly through cell membrane receptors and transcription fac- tor R-Smads and Co-Smad （Smad4）, while an inhibitory Smad, Smad7, acts as a critical negative regulator of TGF-β signaling. Smad7 antagonizes TGF-β signaling by regulating the stability or activity of the receptors or blocking the DNA binding of the functional R-Smad-Smad4 complex in the nucleus. However, the function of Smad7 in the nucleus is not fully understood. Yin Yang 1 （YY1） is a ubiquitously expressed transcription factor with multiple functions. It has been reported that YY1 can inhib- it Smad-dependent transcriptional responses and TGF-β/BMP-induced cell differentiation independently of its DNA binding ability. In this study, we found that Smad7 interacts with YY1 and the interaction is attenuated by TGF-β signaling. Reporter assays and target gene expression analyses revealed that Smad7 and YY1 act in concert to inhibit TGF-β-induced transcription in the nucleus. Furthermore, Smad7 could enhance the interaction of YY1 with the histone deacetylase HDAC1. Consistently, YY 1 and HDAC 1 augmented the transcription repression activity of Smad7 in Gal4-1uciferase reporter analysis. Therefore, our findings define a novel mechanism of Smad7 and YY1 to antagonize TGF-β signaling.

As a prototype of the TGF-βsuperfamily cytokines,TGF-βis well known for its diverse roles in embryogenesis and adult tissue homeostasis.TGF-βevokes cellular responses by signaling mainly through cell membrane receptors and transcription factor R-Smads and Co-Smad(Smad4),while an inhibitory Smad,Smad7,acts as a critical negative regulator of TGF-βsignaling.Smad7 antagonizes TGF-βsignaling by regulating the stability or activity of the receptors or blocking the DNA binding of the functional R-Smad-Smad4 complex in the nucleus.However,the function of Smad7 in the nucleus is not fully understood.Yin Yang 1(YY1)is a ubiquitously expressed transcription factor with multiple functions.It has been reported that YY1 can inhibit Smad-dependent transcriptional responses and TGF-β/BMP-induced cell differentiation independently of its DNA binding ability.In this study,we found that Smad7 interacts with YY1 and the interaction is attenuated by TGF-βsignaling.Reporter assays and target gene expression analyses revealed that Smad7 and YY1 act in concert to inhibit TGF-β-induced transcription in the nucleus.Furthermore,Smad7 could enhance the interaction of YY1 with the histone deacetylase HDAC1.Consistently,YY1 and HDAC1 augmented the transcription repression activity of Smad7 in Gal4-luciferase reporter analysis.Therefore,our findings define a novel mechanism of Smad7 and YY1 to antagonize TGF-βsignaling.