Early replication fragile sites are associated with cancer-related CNVs and SNVs in human embryonic stem cells

  • Stem Cell Reports. 2026 Jul 14;21(7):102968. doi: 10.1016/j.stemcr.2026.102968.
Yu-Ping Dong  1 ,  Menglin Qiu  2 ,  Haoyu Tang  2 ,  Wen Shi  3 ,  Yi Lu  2 ,  Fang Ji  2 ,  Hongwei Liao  2 ,  Songmin Ying  4 ,  Ping Zheng  5 ,  Lin Wang  6
Affiliations
  • 1. State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Animal Models and Human Disease Mechanisms of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China; University of Chinese Academy of Sciences, Beijing 101408, China.
  • 2. Department of Pharmacology & Department of Respiratory and Critical Care Medicine of the Second Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Hangzhou, Zhejiang 310009, China.
  • 3. State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Animal Models and Human Disease Mechanisms of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China.
  • 4. Department of Pharmacology & Department of Respiratory and Critical Care Medicine of the Second Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Hangzhou, Zhejiang 310009, China. Electronic address: [email protected].
  • 5. State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Animal Models and Human Disease Mechanisms of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China; KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China. Electronic address: [email protected].
  • 6. State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Animal Models and Human Disease Mechanisms of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China. Electronic address: [email protected].
PMID: 42314676 DOI: 10.1016/j.stemcr.2026.102968
Abstract

Long-term culture of human embryonic stem cells (hESCs) often induces chromosomal abnormalities, which limits their clinical use. However, the underlying mechanisms are unclear. Early replication fragile sites (ERFSs) are genomic loci susceptible to breakage in early S-phase and serve as hotspots for chromosomal rearrangements, with established links to carcinogenesis. To map ERFSs in hESCs, we established the early S-phase synchronization protocols and identified ERFSs. These ERFSs are enriched in GC content and short interspersed nuclear elements (SINEs) and are frequently located in promoters or enhancers of genes involved in pluripotency, proliferation, and genomic stability. ERFSs also overlap with regions associated with copy number variants (CNVs) and single nucleotide variants (SNVs) linked to cancers. Furthermore, we found that chromatin accessibility contributes to ERFS formation. Collectively, these findings provide a key resource for advancing ERFS research, offering insights into the phenotypic and genomic alterations observed in long-term hESC cultures.

Keywords
copy number variations; early replication fragile sites; genomic stability; human embryonic stem cell; single-nucleotide variants.
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