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Oncogenic mutations disrupt lineage differentiation via epigenetic perturbations

Meng, L.; Plevritis, S. K.; Yu, A.; Meng, J.; Yoo, Y.; Janas, J.; Knowles, D. A.; Huang, H.; Schaukowitch, K. M.

2025-04-23 cell biology
10.1101/2025.04.22.649974 bioRxiv
Show abstract

Understanding lineage differentiation is an ongoing challenge in the field of stem cell research. We acquired eight gain-of-function (GOF) oncogenic mutations associated with DNA methylation alteration from the TCGA datasets. After introducing each oncogene into wild-type stem cells separately, we found that the mutant stem cells are difficult to reprogram to iPSCs and terminally differentiate to induced neuronal cells, and retain proliferation capacity in the process of differentiation. This findings suggests that oncogenic mutations impair the lineage differentiation. After analyzing the resulting DNA methylation profiles, we identified many novel lineage differentiation genes in mutant cells showing DNA methylation alteration compared with wild-type cells, which is consistent with their methylation states in low-grade gliomas (LGGs) compared with control brain. Collectively, our results indicate that oncogenic mutations in stem cells are associated with DNA methylation changes for genes related to multipotency maintenance, differentiation resistance, and tumorigenesis, therefore, displaying impairment in lineage commitment.

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"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.