Master Transcription Factors Determine Cell-Type-Specific Responses to TGF-β Signaling

SummaryTransforming growth factor beta (TGF-β) signaling, mediated through the transcription factors Smad2 and Smad3 (Smad2/3), directs different responses in different cell types. Here we report that Smad3 co-occupies the genome with cell-type-specific master transcription factors. Thus, Smad3 occupies the genome with Oct4 in embryonic stem cells (ESCs), Myod1 in myotubes, and PU.1 in pro-B cells. We find that these master transcription factors are required for Smad3 occupancy and that TGF-β signaling largely affects the genes bound by the master transcription factors. Furthermore, we show that induction of Myod1 in nonmuscle cells is sufficient to redirect Smad3 to Myod1 sites. We conclude that cell-type-specific master transcription factors determine the genes bound by Smad2/3 and are thus responsible for orchestrating the cell-type-specific effects of TGF-β signaling.

Graphical AbstractFigure optionsDownload high-quality image (216 K)Download as PowerPoint slideHighlights
► In ESCs, TGF-β effector Smad3 occupies genomic sites bound by master regulator Oct4
► Oct4 is required for Smad3 occupancy of these genomic sites in ESCs
► Smad3 co-occupies the genome with master transcription factors in multiple cell types
► TGF-β signaling largely affects genes bound by the cell-specific master regulators