{ "abstract": "Rapid hair follicle cycling requires precise fate commitment and differentiation of hair follicle stem cells. While the essential role of transcription factors in establishing cell identity is well recognized, how cells control its protein synthesis to achieve tissue specificity remains unknown. RNA modifications constitute a pivotal layer of post-transcriptional regulation for protein synthesis. Among them, the N7-methylguanosine (m7G) modification has recently emerged as a critical regulator with diverse functional impacts. Here, we reveal a pivotal role of METTL1, the key enzyme for RNA m7G modification, in hair follicle cycle. Conditional knockout of Mettl1 in keratinocytes leads to severe hair follicle developmental dysplasia, impaired regeneration, and disrupted keratinocyte adhesion. Complementarily, keratinocyte-specific knock-in of Mettl1 accelerates hair regeneration. Mechanistically, beyond its effects on tRNAs, METTL1 deficiency destabilizes HOXC13 mRNA through internal m7G modification, which in turn downregulates the HOXC13/FOXN1/DSG4 signaling axis. Our findings establish METTL1-mediated internal mRNA m7G methylation as one of the essential regulatory layers of RNA modification in hair follicle morphogenesis and cycling, operating through the precise post-transcriptional control of a key transcriptional circuit to ensure structural integrity and timely regeneration. Author summary: We investigated whether METTL1, an enzyme that adds a chemical mark (m7G) to RNA molecules, plays a role in hair follicle growth and regeneration. Using mice in which we deleted Mettl1 specifically in keratinocytes, we found that these animals developed abnormal hair follicles and could not regrow hair after injury. Conversely, when we increased Mettl1 expression in keratinocytes, hair regrowth sped up. Looking at the underlying mechanism, we discovered that METTL1 stabilizes the messenger RNA of a key regulator called HOXC13. Without METTL1, HOXC13 levels drop, leading to reduced expression of its downstream targets FOXN1 and DSG4, which are essential for keeping hair shaft cells tightly attached to each other. As a result, keratinocyte adhesion weakens, and hair structure is compromised. Our work identifies METTL1‑mediated m7G modification as a critical post‑transcriptional control that ensures proper hair follicle development and timely cycling by fine‑tuning a key gene regulatory network.", "abstract_shown": true, "affiliations": [ "State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China", "Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China", "West China School of Medicine, Sichuan University, Sichuan University affiliated Chengdu Second People's Hospital, Chengdu, Sichuan, China", "Division of Molecular Signaling and Biochemistry, Kyushu Dental University, Kitakyushu, Fukuoka, Japan", "Department of Dermatology and Venereology, West China Hospital, Sichuan University, Chengdu, Sichuan, China" ], "article_type": "Research Article", "arxiv": null, "author_total": 11, "authors": [ { "affs": [ 0 ], "name": "Xinyan Gan" }, { "affs": [ 1 ], "name": "Qiwen Li" }, { "affs": [ 2 ], "name": "Qiuchan Xiong" }, { "affs": [ 3 ], "name": "Denghao Huang" }, { "affs": [ 4 ], "name": "Zizheng Liu" }, { "name": "Qi Yin" }, { "name": "Shuang Jiang" }, { "name": "Takuma Matsubara" }, { "name": "Shoichiro Kokabu" }, { "name": "Wei Yan" }, { "name": "Quan Yuan" } ], "bibtex": "https://research.draconitic.com/paper/5dwdr3nr8q0mg.bib", "cited_by": 0, "doi": "10.1371/journal.pgen.1012307", "fulltext_url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012307", "id": "5dwdr3nr8q0mg", "issns": [ "1553-7404" ], "landing_url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012307", "language": null, "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "1312|RNA modifications and cancer" ], [ "plos", "/Biology and life sciences/Anatomy/Biological tissue/Epithelium/Epithelial cells/Keratinocytes" ], [ "plos", "/Biology and life sciences/Anatomy/Integumentary system/Hair" ], [ "plos", "/Biology and life sciences/Anatomy/Integumentary system/Hair/Hair follicles" ], [ "plos", "/Biology and life sciences/Anatomy/Integumentary system/Skin/Hair follicles" ], [ "plos", "/Biology and life sciences/Biochemistry/Nucleic acids/RNA/Messenger RNA" ], [ "plos", "/Biology and life sciences/Biochemistry/Nucleic acids/RNA/Non-coding RNA/Transfer RNA" ], [ "plos", "/Biology and life sciences/Bioengineering/Biotechnology/Genetic engineering/Genetically modified organisms/Genetically modified animals" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Epithelial cells/Keratinocytes" ], [ "plos", "/Biology and life sciences/Genetics/Gene expression/Protein translation" ], [ "plos", "/Engineering and technology/Bioengineering/Biotechnology/Genetic engineering/Genetically modified organisms/Genetically modified animals" ], [ "plos", "/Medicine and health sciences/Anatomy/Biological tissue/Epithelium/Epithelial cells/Keratinocytes" ], [ "plos", "/Medicine and health sciences/Anatomy/Integumentary system/Hair" ], [ "plos", "/Medicine and health sciences/Anatomy/Integumentary system/Hair/Hair follicles" ], [ "plos", "/Medicine and health sciences/Anatomy/Integumentary system/Skin/Hair follicles" ], [ "plos", "/Research and analysis methods/Research design/Quantitative analysis" ] ], "openalex": "W7214015782", "pdf_url": "https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1012307&type=printable", "pmcid": null, "pmid": null, "published": "2026-09-22", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/5dwdr3nr8q0mg.ris", "sources": [ { "first_seen": "2026-10-30T12:17:43Z", "native_id": "10.1371/journal.pgen.1012307", "source": "plos", "url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012307" } ], "subjects": [ { "field": "medicine", "origin": "plos:anatomy", "subfield": "physiology" } ], "title": "METTL1-mediated m⁷G modification regulates hair follicle cycle via the HOXC13/FOXN1/DSG4 axis", "title_text": "METTL1-mediated m⁷G modification regulates hair follicle cycle via the HOXC13/FOXN1/DSG4 axis", "type": "peer-reviewed", "updated_at": "2026-10-30T12:17:43Z", "url": "https://research.draconitic.com/paper/5dwdr3nr8q0mg", "venue": "PLOS Genetics", "versions": [] }