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The transforming growth factor beta (TGF-β) family of ligands plays major roles in embryonic development,tissue homeostasis,adult immunity,and wound repair.Dysregulation of TGF-β signaling pathway leads to severe diseases.Its key components have been revealed over the past two decades.This family of cytokines acts by activating receptor activated SMAD (R-SMAD)transcription factors,which in tu modulate the expression of specific sets of target genes.Cells of a multicellular organism have the same genetic information,yet they show structural and functional differences owing to differential expression of their genes.Studies have demonstrated that epigenetic regulation,an integral part of the TGF-β signaling,enables cells to sense and respond to TGF-β signaling in a cell context-dependent manner.R-SMAD,as the central transcription factor of TGF-β signaling,can recruit various epigenetic regulators to shape the transcriptome.In this review,we focus on epigenetic regulatory mechanisms in the TGF-β signaling during mammalian development and diseases and discuss the central role of the interaction between R-SMAD and various epigenetic regulators in this epigenetic regulation.The crosstalk between TGF-β signaling and the epigenome could serve as a versatile fine-tuning mechanism for transcriptional regulation during embryonic development and progression of diseases,particularly cancer.