METTL1-mediated m⁷G modification regulates hair follicle cycle via the HOXC13/FOXN1/DSG4 axis
5 affiliations
- 1State 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
- 2Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
- 3West China School of Medicine, Sichuan University, Sichuan University affiliated Chengdu Second People's Hospital, Chengdu, Sichuan, China
- 4Division of Molecular Signaling and Biochemistry, Kyushu Dental University, Kitakyushu, Fukuoka, Japan
- 5Department of Dermatology and Venereology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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.
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BibTeX
@article{gan2026mettl1mediated,
title = {{METTL1-mediated m⁷G modification regulates hair follicle cycle via the HOXC13/FOXN1/DSG4 axis}},
author = {Xinyan Gan and Qiwen Li and Qiuchan Xiong and Denghao Huang and Zizheng Liu and Qi Yin and Shuang Jiang and Takuma Matsubara and Shoichiro Kokabu and Wei Yan and Quan Yuan},
journal = {PLOS Genetics},
year = {2026},
month = sep,
doi = {10.1371/journal.pgen.1012307},
url = {https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012307},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - METTL1-mediated m⁷G modification regulates hair follicle cycle via the HOXC13/FOXN1/DSG4 axis
AU - Xinyan Gan
AU - Qiwen Li
AU - Qiuchan Xiong
AU - Denghao Huang
AU - Zizheng Liu
AU - Qi Yin
AU - Shuang Jiang
AU - Takuma Matsubara
AU - Shoichiro Kokabu
AU - Wei Yan
AU - Quan Yuan
PY - 2026
DA - 2026/09/22
JO - PLOS Genetics
DO - 10.1371/journal.pgen.1012307
UR - https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012307
AB - 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.
SN - 1553-7404
ER -