{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTrichohyalin (TCHH) is a key structural protein in the inner root sheath of the hair follicle that contributes to the proper assembly of keratin intermediate filaments, thereby influencing hair morphology. Genome‐wide association studies in European populations have identified common variants in TCHH that explain a notable fraction of the variance in hair traits—such as the degree of straightness, waviness, and curliness—while studies in East Asians and admixed populations have revealed that different variants in the TCHH region may also modulate hair straightness. Moreover, analyses in mouse models have demonstrated that the orthologue of TCHH, involved in the regulation of filament assembly during the hair cycle, underlines the evolutionarily conserved role of this protein in hair follicle development and structure."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in determining the natural texture of hair, TCHH is critical for hair shaft formation. Its expression is tightly regulated at the transcriptional level—evidenced by bone morphogenic protein‐mediated activation—and at the posttranslational level via stabilization mechanisms involving nuclear lamina components. Notably, epigenetic studies in pluripotent stem cell–derived human epidermal equivalents have revealed that the TCHH genomic region can retain a methylation signature of the donor tissue in some cell lines while being reset in others, suggesting that precise epigenetic control may be essential for appropriate tissue differentiation and hair follicle function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDisruption of TCHH function can lead to pathological outcomes. In uncombable hair syndrome, for example, recessive mutations in TCHH—as well as in enzymes responsible for its posttranslational modifications—result in structural hair shaft anomalies that manifest as dry, frizzy hair resistant to combing. In addition, TCHH has been implicated as an autoantigen in alopecia areata, where immune reactivity against this anagen‐phase–specific protein may contribute to hair loss. Finally, aberrant methylation of TCHH in circulating cell‐free DNA has emerged as a potential marker for liver metastasis in colorectal cancer, although challenges remain in establishing its prognostic value in stage II/III disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Sachiya Yamamoto, Kyoko Hirai, Yumiko Hasegawa-Oka, et al. 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