Convergence of external and internal stressors on a stress-responsive enhancer of the <i>Sonic hedgehog</i> gene to induce hair disorders

Mammals are constantly exposed to various stressors of internal and external origin. Though hair follicles (HFs) are exquisitely sensitive to stress, it remains largely unknown how stress-induced responses are linked with the intrinsic regulators of HF growth, cycling, and regeneration. Here, we characterize the long-range enhancer of <i>Sonic hedgehog</i> (<i>Shh</i>) gene which encodes a crucial mitogen in the HF, and identify a hair stress-responsive enhancer (<i>HSRE</i>) as a unified target on which various internal and external stressors converge. Together with the immediate early gene <i>Early growth response 1</i> (<i>Egr1</i>), this combination of enhancer and transcription factor mediates hair growth arrest and regeneration defects under several stress conditions, including chemotherapy-induced hair loss, noise-induced hair dystrophy, and retarded hair regeneration in aging and obesity. Under stress, the increased expression of <i>Egr1</i> suppresses <i>Shh</i> gene expression; however, this suppression does not occur when the <i>HSRE</i> is absent. Furthermore, two chemical agents SR11302 and T-5224 which suppress <i>Egr1</i> expression both rescued the hair disorders under the various stressors. We propose that an <i>Egr1</i>-<i>Shh</i> axis integrates distinct stress signals and induces hair disorders via suppression of <i>Shh</i> gene expression, and provide a plausible strategy for therapeutic intervention. Our results establish a paradigm of how stress perturbs organ growth and regeneration through the regulation of key intrinsic morphogenetic factors.