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Regulation of Twist1 and Snail1 Gene Expression in Cardiac Fibroblasts by Scleraxis

Cardiac fibrosis causes progressive cardiac stiffening due to abnormal deposition of extracellular matrix (ECM) and alters electrical conduction of the action potential, resulting in heart failure and death. Cardiac fibroblasts largely arise from epithelial precursors during development via epithelial‐to‐mesenchymal transition (EMT), and upon injury or stress, are further converted to an activated state – myofibroblasts – which express a variety of pro‐fibrotic genes responsible for ECM synthesis and deposition. Our previous data suggested that the transcription factor scleraxis plays a key role in regulating cardiac fibroblast cell fate, including EMT and myofibroblast conversion. Here, we examined the role of scleraxis in transactivating expression of genes encoding key EMT regulators including the basic helix‐loop‐helix transcription factor Twist1 and the zinc finger transcription factor Snail1. Over‐expression of scleraxis in NIH3T3 fibroblasts up‐regulated Twist1 and Snail1 expression. Using luciferase reporter assays coupled with point mutagenesis, we found that scleraxis is sufficient to directly transactivate the Twist1 and Snail1 gene promoters, and identified the responsible scleraxis binding sites in each promoter. Loss of scleraxis conversely attenuated expression of these genes. Together, our data indicates that scleraxis controls EMT via direct upstream regulation of these key EMT regulatory genes.