title: 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 serum response factor (SRF) and its cofactor MKL1 (also known as 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 for the published human isoform, MKL1_L. Using a human adipose-derived mesenchymal stem cell differentiation model, we show that TGF-β specifically upregulates 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 the extracellular matrix (ECM) modifiers MMP16 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.
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Department of Mechanisms of Cancer, Maulbeerstrasse 66, CH-4058, Basel, Switzerland.
authors.forename: Matthias A
authors.initials: MA
authors.lastname: Scharenberg
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Pippenger
authors.forename: Ragna
authors.initials: R
authors.lastname: Sack
authors.forename: Dominik
authors.initials: D
authors.lastname: Zingg
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Ferralli
authors.forename: Susanne
authors.initials: S
authors.lastname: Schenk
authors.forename: Ivan
authors.initials: I
authors.lastname: Martin
authors.forename: Ruth
authors.initials: R
authors.lastname: Chiquet-Ehrismann
mesh_terms: D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D001483:Base Sequence; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D018387:Codon, Initiator; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D053513:Matrix Metalloproteinase 16 / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D058628:Myofibroblasts / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015534:Trans-Activators; D014158:Transcription, Genetic; D053773:Transforming Growth Factor beta1 / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D018387:Codon, Initiator; D004268:DNA-Binding Proteins; C507102:MMP16 protein, human; C431575:MRTFA protein, human; D015514:Oncogene Proteins, Fusion; D020033:Protein Isoforms; C508960:TGFB1 protein, human; D015534:Trans-Activators; D053773:Transforming Growth Factor beta1; D053513:Matrix Metalloproteinase 16
keywords: Gene regulation; MKL1; MRTF-A; Myofibroblast differentiation