2. Academic Validation
  3. TRIM37-PARP1-TET1 axis maintains stemness and prevents osteoporosis by inhibiting DNMT1 alternative splicing via 5hmC regulation

TRIM37-PARP1-TET1 axis maintains stemness and prevents osteoporosis by inhibiting DNMT1 alternative splicing via 5hmC regulation

  • Nat Commun. 2025 Dec 16;16(1):11420. doi: 10.1038/s41467-025-66281-y.
Chun-Te Ho 1 2,  Ling-Hui Li 3,  Wei-Chao Chang 4,  Heng-Hsiung Wu 1 5,  Ya-Huey Chen 1 5 6,  Shih-Chieh Hung 7 8
Affiliations

Affiliations

  • 1 Drug Development Center, Institute of New Drug Development, Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
  • 2 Integrative Stem Cell Center, Department of Orthopaedics, China Medical University Hospital, Taichung, Taiwan.
  • 3 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
  • 4 Center for Molecular Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan.
  • 5 Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
  • 6 Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan.
  • 7 Drug Development Center, Institute of New Drug Development, Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan. [email protected].
  • 8 Integrative Stem Cell Center, Department of Orthopaedics, China Medical University Hospital, Taichung, Taiwan. [email protected].
PMID: 41402268 DOI: 10.1038/s41467-025-66281-y
Abstract

The significance of DNA hydroxymethylation in replicative senescence of mesenchymal stem cells (MSCs) and aging-related osteoporosis remains unknown. Here, we reveal 5hmC levels positively regulate MSC self-renewal and osteoblast differentiation. Mechanistically, PARP1 recruits TET1 to hydrolyze methylated nucleotides on DNMT1 exons, aiding CTCF in preventing DNMT1 alternative splicing in early MSCs. Additionally, ATM phosphorylates TRIM37 at Th203, promoting its nuclear entry and the monoubiquitination of PARP1, stabilizing the protein. CTCF or TRIM37 knockdown induces replicative senescence of MSCs with loss of full-length DNMT1. Co-treatment with resveratrol (ATM activator) and vitamin C (TET1 Activator) rejuvenates late MSCs via the TRIM37/PARP1/DNMT1 pathway and alleviates osteoporosis in aged mice. Gene knockout experiments further reveal the participation of TRIM37 and PARP1 in MSC aging, contributing significantly to bone maintenance and repair in vivo. This study emphasizes the role of DNA hydroxymethylation in stemness, suggesting therapeutic strategies, especially for osteoporosis.

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