TGF-β-induced differentiation into myofibroblasts involves specific regulation of two MKL1 isoforms

Abstract

Cellular transformation into myofibroblasts is a central physiological process enabling tissue repair. Its deregulation promotes fibrosis and carcinogenesis. TGF-β is the main inducer of the contractile gene program that drives myofibroblast differentiation from various precursor cell types. Crucial regulators of this transcriptional program are SRF and its cofactor MKL1/MRTF-A. However, the exact mechanism of the crosstalk between TGF-β signaling and MKL1 remains unclear. Here, we report the discovery of a novel MKL1 variant/isoform, MKL1_S, transcribed from an alternative promoter and uncover a novel translation start of the published human isoform, MKL1_L. Using a human adipose-derived mesenchymal stem cell differentiation model, we show that TGF-β specifically up-regulates MKL1_S during the initial phase of myofibroblast differentiation. We identified a functional N-terminal motif in MKL1_S that allows specific induction of a group of genes including ECM modifiers MMP-16 and SPOCK3/testican-3. We propose that TGF-β-mediated induction of MKL1_S initiates progression to later stages of differentiation towards a stationary myofibroblast.