Graduate School of Biomedical Science & Engineering, Hanyang University, Seoul, Korea.
Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, Korea.
Nat Commun. 2024 Jan 2;15(1):158. doi: 10.1038/s41467-023-44600-5.
UPF1 and LIN28A are RNA-binding proteins involved in post-transcriptional regulation and stem cell differentiation. Most studies on UPF1 and LIN28A have focused on the molecular mechanisms of differentiated cells and stem cell differentiation, respectively. We reveal that LIN28A directly interacts with UPF1 before UPF1-UPF2 complexing, thereby reducing UPF1 phosphorylation and inhibiting nonsense-mediated mRNA decay (NMD). We identify the interacting domains of UPF1 and LIN28A; moreover, we develop a peptide that impairs UPF1-LIN28A interaction and augments NMD efficiency. Transcriptome analysis of human pluripotent stem cells (hPSCs) confirms that the levels of NMD targets are significantly regulated by both UPF1 and LIN28A. Inhibiting the UPF1-LIN28A interaction using a CPP-conjugated peptide promotes spontaneous differentiation by repressing the pluripotency of hPSCs during proliferation. Furthermore, the UPF1-LIN28A interaction specifically regulates transcripts involved in ectodermal differentiation. Our study reveals that transcriptome regulation via the UPF1-LIN28A interaction in hPSCs determines cell fate.
UPF1 和 LIN28A 是参与转录后调控和干细胞分化的 RNA 结合蛋白。大多数关于 UPF1 和 LIN28A 的研究分别集中在分化细胞和干细胞分化的分子机制上。我们揭示了 LIN28A 在 UPF1-UPF2 复合物形成之前直接与 UPF1 相互作用，从而减少 UPF1 的磷酸化并抑制无意义介导的 mRNA 降解（NMD）。我们确定了 UPF1 和 LIN28A 的相互作用域；此外，我们开发了一种肽，可破坏 UPF1-LIN28A 相互作用并增强 NMD 效率。人多能干细胞（hPSC）的转录组分析证实，NMD 靶标水平受到 UPF1 和 LIN28A 的显著调节。通过使用 CPP 缀合的肽抑制 UPF1-LIN28A 相互作用，通过在增殖过程中抑制 hPSC 的多能性来促进自发分化。此外，UPF1-LIN28A 相互作用特异性调节涉及外胚层分化的转录本。我们的研究揭示了 hPSCs 中通过 UPF1-LIN28A 相互作用进行的转录组调节决定细胞命运。
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