Multicellular organisms including human are constituted of cells with different function and identity. Cell identity depends on gene expression programs. Single nucleotide polymorphisms in super-enhancers have recently been associated with a wide range of human diseases (Hnisz et al., 2013, Cell, 155, 934-47), suggesting the destabilization of cell identity causes disease. However, the mechanisms that suppress cell-type gene expression programs are poorly understood. Here we show that serum response factor (Srf), a transcription factor that is activated by various extracellular stimuli such as extracellular matrix stiffness, can suppress cell-type gene expressions. Depletion of β-actin increased the nuclear localization of Mkl1, a cofactor of Srf, resulting in the activation of Srf. Misactivation of Srf, which can be achieved by the suppression of Actb (β-actin-encoding gene) as well as overexpression of Mkl1 or Srf downregulated cell-type gene expressions. Transgenic mice overexpressing Srf exhibited various symptoms associated with cell identity loss. Moreover, analyses of publicly available microarray data of human diseases suggested that the misactivation of Srf is also associated with various human diseases. Srf could be a possible target molecule for therapy of various diseases.