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  3. DNA G-quadruplex profiling in skeletal muscle stem cells reveals functional and mechanistic insights

DNA G-quadruplex profiling in skeletal muscle stem cells reveals functional and mechanistic insights

  • Genome Biol. 2025 Sep 5;26(1):269. doi: 10.1186/s13059-025-03753-w.
Xiaona Chen # 1 2 3,  Feng Yang # 4 5,  Suyang Zhang # 6 4 7,  Xiaofan Guo 6 4,  Jieyu Zhao 8,  Yulong Qiao 6 4,  Liangqiang He 7,  Yang Li 6 4 7,  Qin Zhou 6 4,  Michael Tim-Yun Ong 6 7,  Chun Kit Kwok 8 9,  Hao Sun 10,  Huating Wang 11 12 13
Affiliations

Affiliations

  • 1 Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, China. xiaonachen@cuhk.edu.hk.
  • 2 Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China. xiaonachen@cuhk.edu.hk.
  • 3 InnoHK Center for Neuromusculoskeletal Restorative Medicine Limited, Hong Kong Science Park, Hong Kong SAR, China. xiaonachen@cuhk.edu.hk.
  • 4 Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • 5 Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • 6 Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • 7 InnoHK Center for Neuromusculoskeletal Restorative Medicine Limited, Hong Kong Science Park, Hong Kong SAR, China.
  • 8 Department of Chemistry and State Key Laboratory of Marine Environmental Health, City University of Hong Kong, Kowloon Tong, Hong Kong SAR, China.
  • 9 Shenzhen Research Institute of City University of Hong Kong, Shenzhen, China.
  • 10 Faculty of Medicine, Warshel Institute for Computational Biology, Chinese University of Hong Kong (Shenzhen), Guangdong, China. sunhao100@cuhk.edu.cn.
  • 11 Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, China. huating.wang@cuhk.edu.hk.
  • 12 Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China. huating.wang@cuhk.edu.hk.
  • 13 InnoHK Center for Neuromusculoskeletal Restorative Medicine Limited, Hong Kong Science Park, Hong Kong SAR, China. huating.wang@cuhk.edu.hk.
  • # Contributed equally.
PMID: 40913227 DOI: 10.1186/s13059-025-03753-w
Abstract

Background: DNA G-quadruplexes (G4s) are non-canonical secondary structures formed in guanine-rich DNA sequences and play important roles in modulating biological processes through a variety of gene regulatory mechanisms. Emerging G4 profiling allows global mapping of endogenous G4 formation.

Results: Here in this study, we map the G4 landscapes in adult skeletal muscle stem cells (MuSCs), which are essential for injury-induced muscle regeneration. Throughout the myogenic lineage progression of MuSCs, we uncover dynamic endogenous G4 formation with a pronounced G4 induction when MuSCs become activated and proliferating. We further demonstrate that the G4 induction promotes MuSC activation thus the regeneration process. Mechanistically, we found that promoter-associated G4s regulate gene transcription through facilitating chromatin looping. Furthermore, we found that G4 sites are enriched for transcription factor (TF) binding events in activated MuSCs; MAX binds to G4 structures to synergistically facilitate chromatin looping and gene transcription, thus promoting MuSC activation and regeneration. The above uncovered global regulatory functions/mechanisms are further dissected on the paradigm of Ccne1 promoter, demonstrating that Ccne1 is a bona fide G4/MAX regulatory target in activated MuSCs.

Conclusions: Altogether, our findings for the first time demonstrate the prevalent and dynamic formation of G4s in adult MuSCs and the mechanistic role of G4s in modulating gene expression and MuSC activation/proliferation.

Keywords

Chromatin looping; DNA G-quadruplex; MAX; Muscle regeneration; Skeletal muscle stem cells.

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