Epigenetic Reshaping through Damage: Promoting Cell Fate Transition by BrdU and IdU incorportion

Abstract

Abstract Background:Thymidine analogs have long been recognized for their ability to randomly incorporate into DNA. However, the precise mechanisms through which thymidine analogs facilitate cell fate transition remains unclear. Results:Here, we discovered a strong correlation between the dosage dependence of thymidine analogs and their ability to overcome reprogramming barrier. Meanwhile, we found that homologous recombination repair (HRR) pathway causes an overall epigenetic reshaping of cells and enabling them to overcome greater barriers. Moreover, extraembryonic endoderm (XEN) state appears to be a selective response behavior of cells to DNA damage repair (DDR), providing a shortcut for cells to overcome reprogramming barriers, creates a hypomethylated environment that promotes cell fate transition in multiple reprogramming systems. We term this mechanism as Epigenetic Reshaping through Damage (ERD). Conclustion:Overall, our study sheds light on the dynamic interplay between thymidine analogs, DDR, and epigenetic modifications, providing valuable insights into the mechanisms underlying cell fate transition.