Convergence of external and internal stressors on a stress-responsive enhancer of the Sonic hedgehog gene to induce hair disorders
2026-03-31
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 Sonic hedgehog ( Shh ) gene which encodes a crucial mitogen in the HF, and identify a hair stress-responsive enhancer ( HSRE ) as a unified target on which various internal and external stressors converge. Together with the immediate early gene Early growth response 1 ( Egr1 ), 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 Egr1 suppresses Shh gene expression; however, this suppression does not occur when the HSRE is absent. Furthermore, two chemical agents SR11302 and T-5224 which suppress Egr1 expression both rescued the hair disorders under the various stressors. We propose that an Egr1 – Shh axis integrates distinct stress signals and induces hair disorders via suppression of Shh 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.