ABSTRACT

Liver is the central organ responsible for whole-body metabolism, and its constituent hepatocytes are the major players that carry out liver functions. Although they are highly differentiated and rarely divide, hepatocytes re-enter the cell cycle following hepatic loss due to liver damage or injury. However, the exact molecular mechanisms underlying cell cycle re-entry remain undefined. Gdown1 is an RNA polymerase II (Pol II)-associated protein that has been linked to the function of the Mediator transcriptional coactivator complex. We recently found that Gdown1 ablation in mouse liver leads to down-regulation of highly expressed liver-specific genes and a concomitant cell cycle re-entry associated with the induction of cell cycle-related genes. Unexpectedly, in view of a previously documented inhibitory effect on transcription initiation by Pol II in vitro, we found that Gdown1 is associated with elongating Pol II on the highly expressed genes and that its ablation leads to a reduced Pol II occupancy that correlates with the reduced expression of these genes. Based on these observations, we discuss the in vitro and in vivo functions of Gdown1 and consider mechanisms by which the dysregulated Pol II recruitment associated with Gdown1 loss might induce quiescent cell re-entry into the cell cycle.

 抽象的

肝脏是负责全身代谢的中枢器官，其组成的肝细胞是执行肝脏功能的主要参与者。尽管肝细胞高度分化且很少分裂，但由于肝损伤或损伤导致肝损失后，肝细胞会重新进入细胞周期。然而，细胞周期重新进入的确切分子机制仍不清楚。 Gdown1 是一种 RNA 聚合酶 II (Pol II) 相关蛋白，与介导转录共激活复合物的功能有关。我们最近发现小鼠肝脏中 Gdown1 的消除导致高表达的肝脏特异性基因下调，并伴随细胞周期重新进入与细胞周期相关基因的诱导相关。出乎意料的是，鉴于先前记录的体外 Pol II 对转录起始的抑制作用，我们发现 Gdown1 与高表达基因上 Pol II 的延长有关，并且其消融导致 Pol II 占用率降低，这与 Pol II 占用率的降低相关。这些基因的表达。基于这些观察结果，我们讨论了 Gdown1 的体外和体内功能，并考虑了与 Gdown1 丢失相关的 Pol II 募集失调可能诱导静止细胞重新进入细胞周期的机制。