{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe Hairless (Hr) gene encodes a nuclear protein that functions as a transcriptional corepressor critical for hair follicle morphogenesis, cycling, and overall skin homeostasis. By governing the balance between epithelial stem cell proliferation, differentiation, and apoptosis, HR tightly regulates the timing of hair follicle regeneration. HR modulates key signaling pathways—including the Wnt pathway through regulators such as Wise and Sfrp2—and controls the expression of differentiation markers and keratinocyte terminal genes. Mutations or altered expression of HR (whether by loss‐of‐function, gain‐of‐function, or missense mutations) disturb these processes and culminate in various forms of alopecia and skin abnormalities."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its direct role in hair follicle biology, HR acts as a critical regulator of nuclear receptor signaling. It interacts with receptors for thyroid hormone and vitamin D, recruiting histone deacetylases to repress transcription of target genes. This activity influences diverse developmental processes including neural differentiation and epidermal maturation. HR-mediated regulation extends to key transcription factors—such as Foxe1 and Dlx3—and its altered function results in dysregulation of chromatin remodeling and cell cycle control. Moreover, HR’s responsiveness to environmental cues (for example, ultraviolet B irradiation) can lead to aberrant activation of NFκB and its downstream effectors, thereby contributing to tumorigenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "16"}, {"type": "fg_f", "ref": "6"}, {"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical roles in the skin, HR is integrated into broader regulatory networks that include post‐transcriptional control and metabolic homeostasis. For instance, HR forms a negative regulatory loop with polyamines such as putrescine, wherein increased polyamine levels can suppress HR expression and, conversely, reduced HR elevates enzymes like ornithine decarboxylase. In parallel, HR influences adipogenesis by modulating expression of central factors like PPARγ, thereby contributing to resistance against high‐fat diet–induced obesity and insulin resistance. Notably, one study has characterized a distinct subunit—PGs1, encoded by GTRGEO22"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": "—that is essential for the localization of polyglutamylase activity in neurons, axonemes, and centrioles; this underscores the diversity of protein complexes that share mechanistic parallels with HR’s regulatory roles."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "20", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Joanna M Zarach, Gerard M J Beaudoin, Pierre A Coulombe, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Hairless triggers reactivation of hair growth by promoting Wnt signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0507609102"}], "href": "https://doi.org/10.1073/pnas.0507609102"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16195376"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16195376"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "In Cheol Baek, Jeong Ki Kim, Kyu-Hyuk Cho, et al. 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