KDM8 acts as a co-regulator of transcription factor SOX2 for promoting cell pluripotency

  • Stem Cell Reports. 2026 Jul 14;21(7):102963. doi: 10.1016/j.stemcr.2026.102963.
Songqin Yang  1 ,  Zhikai Ye  2 ,  Lu Lin  1 ,  Zhenlong Jiang  3 ,  Erkang Wang  1 ,  Jin Wang  4
Affiliations
  • 1. State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China; School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, Anhui 230026, China.
  • 2. State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China; Center for Theoretical Interdisciplinary Sciences Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325001, China.
  • 3. State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China. Electronic address: [email protected].
  • 4. Department of Chemistry, Physics and Applied Mathematics, State University of New York at Stony Brook., Stony Brook, NY 11794-3400, USA. Electronic address: [email protected].
PMID: 42314671 DOI: 10.1016/j.stemcr.2026.102963
Abstract

iPSCs have drawn significant attention for their biomedical potential, yet reprogramming remains inefficient and the underlying mechanisms are incompletely defined. KDM8, a Histone Demethylase, is known to play critical roles in processes such as cell-cycle regulation and embryonic development; nevertheless, its function in reprogramming has not been reported. Our investigations demonstrate that KDM8 significantly enhances the reprogramming efficiency mediated by the canonical Yamanaka factors. Remarkably, KDM8, in combination with OCT4 alone, is sufficient to reprogram somatic cells. Further analyses reveal that KDM8 facilitates reprogramming through a dual regulatory mechanism. On one hand, KDM8 leverages its canonical enzymatic activity to reduce the epigenetic barriers to iPSC formation. More importantly, KDM8 functions as a co-regulator of the transcription factor SOX2, promoting SOX2's DNA-binding affinity and transcriptional regulation of downstream pluripotency target genes. Accordingly, we propose a novel regulatory framework that uncovers novel mechanisms and functions of KDM8 in cellular reprogramming.

Keywords
KDM8; SOX2; co-regulator; epigenetic barrier; iPSCs.
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