Transcriptional and epigenetic mechanisms governing epidermal stem cell regulation.

Epithelial stem cells in the interfollicular epidermis (IFE) and hair follicle (HF) play key roles in maintaining and regenerating the skin barrier by balancing self-renewal and differentiation. These fate decisions are governed by transcriptional and epigenetic mechanisms that respond to context-dependent signals from the skin microenvironment. In the IFE, basal stem cell divisions follow a stable pattern but rely on tightly regulated transcription factors and chromatin states to ensure proper epidermal maintenance. In contrast, HF stem cells exhibit a higher degree of plasticity that allows for rapid adaptation to changing environments, including IFE regeneration following injury. While this plasticity is critical for epidermal integrity, it can also drive disease onset if transcriptional programs become disrupted. This review provides a comprehensive analysis of how transcriptional and epigenetic regulators guide stem cell fate decisions required in the IFE and HF that promote epidermal homeostasis. We also explore how these programs are altered in various pathological contexts in the skin. By comparing differentiation mechanisms in the IFE and HF compartments, we highlight how dynamic control of gene expression sustains skin homeostasis.