BCOR mutations establish a persistent culture-adaptive state in human induced pluripotent stem cells
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…
Human induced pluripotent stem cells (hiPSCs) play a crucial role in disease modelling and regenerative medicine, relying on molecular integrity during long-term culture. BCOR mutations, prevalent culture-acquired alterations, have uncertain functional consequences. This study reveals that hiPSC BCOR mutations predominantly consist of truncating indels in exon 7, forming a distinct mutational landscape from cancer.
Multi-omics profiling uncovers that BCOR loss triggers extensive chromatin, transcriptomic, and proteomic remodeling, activating developmental, pluripotency-associated, and mitochondrial metabolism programs concurrently. To enable regular monitoring, a cost-effective TaqMan qPCR assay is developed to identify BCOR-mutant hiPSCs consistently across independent cell lines.
Notably, correcting BCOR mutations via CRISPR-Cas9 only partially restores the wild-type molecular state, emphasizing the significance of early detection and continuous monitoring of adaptive mutations in hiPSC cultures.
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