Scleraxis: a force-responsive cell phenotype regulator Hamza A Safi 1 , Raghu S Nagalingam 1 and Michael P Czubryt Changes in cell phenotype underlie many of the body’s responses to altered environmental conditions, stress, or damage, resulting in both physiological and pathophysiological alterations to tissue function. Transcriptional regulators play a critical role in reprogramming cell identity and behavior. Emerging evidence has implicated the transcription factor scleraxis as a novel and powerful determiner of cell phenotype in cells that produce large quantities of extracellular matrix, including tenocytes and cardiac fibroblasts. In this review, we examine the role of scleraxis in epithelial-to-mesenchymal transition and in altering cell phenotype, and discuss the implications of this role in tissue repair and pathology. This specialized role for scleraxis makes it a potential target for therapies aimed at improving wound healing or attenuating tissue fibrosis. Address Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada Corresponding author: Czubryt, Michael P (mczubryt@sbrc.ca) 1 These authors were equal contributors to this work. Current Opinion in Physiology 2018, 01:104–110 This review comes from a themed issue on Cardiac physiology Edited by David Eisner and Merry Lindsay https://doi.org/10.1016/j.cophys.2017.07.004 2468-8673/ã 2017 Elsevier Ltd. All rights reserved. Introduction Changes in individual cell phenotypes underlie many of the long-term physiological and pathophysiological responses of the body to altered conditions of both the external and internal environments. These changes may be relatively conservative, such as the hypertrophy of myocytes that occurs in response to exercise — while the cell increases in size, produces more mitochondria and may alter the way fuel is processed to provide energy, it remains fundamentally recognizable in appearance and activity as a muscle cell. Conversely, oncogenic transfor- mation typically results in widespread alterations in cell appearance, behavior and viability, such that the original phenotype is virtually unrecognizable in the cancer cell. Underlying all such phenotypic changes, however, are fundamental alterations in intracellular signaling and gene expression. Cell phenotype switching may occur relatively rapidly, but phenotypes themselves are typically stable for long periods of time. These changes require large-scale altera- tions in gene expression that are achieved by the con- certed actions of a host of transcription factors, repressors and co-factors in response to activation or inhibition of upstream signaling pathways. Transcriptional control thus provides a powerful mechanism by which cell behavior is governed, such that individual transcription factors, alone, may be capable of inducing broad and pervasive changes in cell phenotype. Some transcrip- tional regulators govern the expression of a plethora of downstream genes, and thus exhibit pleiotropic effects on cell function and behavior, while others appear to control a much narrower subset of genes. Transcription regulators in this latter category thus may represent potential therapeutic targets when their downstream genes are involved in maladaptation to stress or damage. Emerging data from our laboratory and others indicates that scleraxis may not only behave as a cell phenotype regulator, but may also be tractable as a target for the treatment of fibrosis. Scleraxis is a basic helix-loop-helix (bHLH) transcription factor that appears to be most highly expressed in tissues that are routinely subjected to large physical forces, including tendons, ligaments, and cardiac valves [1,2]. Scleraxis is also highly expressed in regions rich in con- nective tissue such as the tongue, limbs, diaphragm and bronchial cartilage [3]. This curious expression pattern suggests that scleraxis may be involved in the response of cells and tissues to mechanical stress. From a yeast 2-hybrid screen of an embryonic mouse cDNA library, scleraxis was first identified as an inter- acting partner of the ubiquitous E-box binding transcrip- tion factor E12 [3]. Similar to other class I bHLH pro- teins, scleraxis possesses a basic amino acid-rich DNA- binding site which allows binding to the E-box consensus sequence (CANNTG, N = any nucleotide) within target gene promoters. Scleraxis also possesses a helix-loop- helix protein interaction domain, which facilitates its binding to transcriptional regulatory partners such as E12, E47, CREB and Smad3 [4–6,7  ]. This ability to physically interact with other transcriptional regulators may provide the mechanism by which scleraxis can control expression of different subsets of genes in differ- ent tissues, resulting in different phenotypic effects. This interaction may also explain why scleraxis appears to bind to only a subset of E-box sequences, which are fairly common cis regulatory elements throughout the genome. Available online at www.sciencedirect.com ScienceDirect Current Opinion in Physiology 2018, 1:104–110 www.sciencedirect.com