Cellular Reprogramming, Stem Cells and Oncogenesis Laboratory, Equipe Labellisée la Ligue Contre le Cancer, LabEx Dev2Can, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
Lunenfeld-Tanenbaum Research Institute, University of Toronto, Toronto, Ontario, Canada.
Nat Cell Biol. 2022 Sep;24(9):1350-1363. doi: 10.1038/s41556-022-00986-w. Epub 2022 Sep 8.
Coordinated changes of cellular plasticity and identity are critical for pluripotent reprogramming and oncogenic transformation. However, the sequences of events that orchestrate these intermingled modifications have never been comparatively dissected. Here, we deconvolute the cellular trajectories of reprogramming (via Oct4/Sox2/Klf4/c-Myc) and transformation (via Ras/c-Myc) at the single-cell resolution and reveal how the two processes intersect before they bifurcate. This approach led us to identify the transcription factor Bcl11b as a broad-range regulator of cell fate changes, as well as a pertinent marker to capture early cellular intermediates that emerge simultaneously during reprogramming and transformation. Multiomics characterization of these intermediates unveiled a c-Myc/Atoh8/Sfrp1 regulatory axis that constrains reprogramming, transformation and transdifferentiation. Mechanistically, we found that Atoh8 restrains cellular plasticity, independent of cellular identity, by binding a specific enhancer network. This study provides insights into the partitioned control of cellular plasticity and identity for both regenerative and cancer biology.
细胞可塑性和身份的协调变化对于多能性重编程和致癌转化至关重要。然而，协调这些交织变化的事件序列从未被比较性地剖析过。在这里，我们在单细胞分辨率下解卷积了重编程（通过 Oct4/Sox2/Klf4/c-Myc）和转化（通过 Ras/c-Myc）的细胞轨迹，并揭示了这两个过程在分叉之前是如何交叉的。这种方法使我们能够识别转录因子 Bcl11b 作为细胞命运变化的广谱调节剂，以及一个相关的标记，以捕获在重编程和转化过程中同时出现的早期细胞中间产物。对这些中间产物的多组学特征分析揭示了一个 c-Myc/Atoh8/Sfrp1 调节轴，该轴限制了重编程、转化和转分化。从机制上讲，我们发现 Atoh8 通过结合特定的增强子网络，独立于细胞身份来限制细胞可塑性。这项研究为再生和癌症生物学中的细胞可塑性和身份的分区控制提供了深入了解。
