School of Medicine, Nankai University, Tianjin, China.
Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China.
J Mol Cell Biol. 2019 Jun 1;11(6):474-488. doi: 10.1093/jmcb/mjy069.
Lin28a is a pluripotent factor that promotes somatic cell reprogramming. Unlike other pluripotent factors, Lin28a expression is transient and accumulated in primed embryonic stem (ES) cells, but its exact function and mechanism in the conversion of ES cells from naïve to primed state remain unclear. Here, we present evidence for Dppa3, a protein originally known for its role in germ cell development, as a downstream target of Lin28a in naïve-primed conversion. Using rescue experiment, we demonstrate that Dppa3 functions predominantly downstream of Lin28a during naïve-primed state conversion. Higher level of Lin28a prevents let-7 maturation and results in Dnmt3a/b (target of let-7) upregulation, which in turn induces hypermethylation of the Dppa3 promoter. Dppa3 demarcates naïve versus primed pluripotency states. These results emphasize that Lin28a plays an important role during the naïve-primed state conversion of ES cells, which is partially mediated by a Lin28a-let-7-Dnmt3a/b-Dppa3 axis.
Lin28a 是一种多能因子，可促进体细胞重编程。与其他多能因子不同，Lin28a 的表达是短暂的，并在初始胚胎干细胞（ES 细胞）中积累，但它在 ES 细胞从原始状态向初始状态转化中的确切功能和机制仍不清楚。在这里，我们提出了证据表明，Dppa3 是一种最初在生殖细胞发育中发挥作用的蛋白，是 Lin28a 在原始-初始转化中的下游靶标。通过挽救实验，我们证明 Dppa3 在原始-初始状态转换期间主要在 Lin28a 的下游发挥作用。更高水平的 Lin28a 可阻止 let-7 的成熟，并导致 Dnmt3a/b（let-7 的靶标）的上调，进而诱导 Dppa3 启动子的过度甲基化。Dppa3 标记原始与初始多能性状态。这些结果强调了 Lin28a 在 ES 细胞原始-初始状态转换中发挥重要作用，这部分是通过 Lin28a-let-7-Dnmt3a/b-Dppa3 轴介导的。
