BCOR mutations establish a persistent culture-adaptive state in human induced pluripotent stem cells

Abstract

Human induced pluripotent stem cells (hiPSCs) are widely used for disease modelling and regenerative medicine, yet their utility depends on maintaining molecular integrity during long-term culture. BCOR (BCL6 Co-Repressor) mutations are among the most recurrent culture-acquired alterations in hiPSCs, but their functional consequences remain poorly understood. Here, we show that hiPSC BCOR mutations are predominantly truncating indels enriched in exon 7, defining a mutational landscape distinct from that observed in cancer. Multi-omics profiling reveals that BCOR loss drives widespread chromatin, transcriptomic and proteomic remodelling, with coordinated activation of developmental, pluripotency-associated and mitochondrial metabolism programmes. To facilitate routine surveillance, we develop a cost-effective TaqMan qPCR assay that accurately identifies BCOR-mutant hiPSCs across independent cell lines. Finally, we demonstrate that correction of BCOR mutation by CRISPR-Cas9 only partially restores the wildtype molecular state, highlighting the importance of early detection and monitoring of adaptive mutations in hiPSC cultures.

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BibTeX

@misc{badja2026bcor,
  title = {{BCOR mutations establish a persistent culture-adaptive state in human induced pluripotent stem cells}},
  author = {C. Badja and S. Boushaki and Y. Kumar and T. I. Roumeliotis and A. J. Curle and A. E. Guiloff and A. Degasperi and S. Momen and F. Robert and Y. Memari and S. Shooter and Z. Kozik and S. J. Zhao and P. J. Toong and I. Baker and B. Hendrich and R. A. Barker and J. Choudhary and G. C. C. Koh and S. Nik-Zainal},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.04.739550},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.04.739550v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - BCOR mutations establish a persistent culture-adaptive state in human induced pluripotent stem cells
AU  - C. Badja
AU  - S. Boushaki
AU  - Y. Kumar
AU  - T. I. Roumeliotis
AU  - A. J. Curle
AU  - A. E. Guiloff
AU  - A. Degasperi
AU  - S. Momen
AU  - F. Robert
AU  - Y. Memari
AU  - S. Shooter
AU  - Z. Kozik
AU  - S. J. Zhao
AU  - P. J. Toong
AU  - I. Baker
AU  - B. Hendrich
AU  - R. A. Barker
AU  - J. Choudhary
AU  - G. C. C. Koh
AU  - S. Nik-Zainal
PY  - 2026
DA  - 2026/09/04
PB  - bioRxiv
DO  - 10.64898/2026.09.04.739550
UR  - https://www.biorxiv.org/content/10.64898/2026.09.04.739550v1
AB  - Human induced pluripotent stem cells (hiPSCs) are widely used for disease modelling and regenerative medicine, yet their utility depends on maintaining molecular integrity during long-term culture. BCOR (BCL6 Co-Repressor) mutations are among the most recurrent culture-acquired alterations in hiPSCs, but their functional consequences remain poorly understood. Here, we show that hiPSC BCOR mutations are predominantly truncating indels enriched in exon 7, defining a mutational landscape distinct from that observed in cancer. Multi-omics profiling reveals that BCOR loss drives widespread chromatin, transcriptomic and proteomic remodelling, with coordinated activation of developmental, pluripotency-associated and mitochondrial metabolism programmes. To facilitate routine surveillance, we develop a cost-effective TaqMan qPCR assay that accurately identifies BCOR-mutant hiPSCs across independent cell lines. Finally, we demonstrate that correction of BCOR mutation by CRISPR-Cas9 only partially restores the wildtype molecular state, highlighting the importance of early detection and monitoring of adaptive mutations in hiPSC cultures.
ER  -

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