Liver injury triggers adaptive remodeling of the hepatic transcriptome for repair/regeneration. We demonstrate that this involves particularly profound transcriptomic alterations where acute induction of genes involved in handling of endoplasmic reticulum stress (ERS) is accompanied by partial hepatic dedifferentiation. Importantly, widespread hepatic gene downregulation could not simply be ascribed to cofactor squelching secondary to ERS gene induction, but rather involves a combination of active repressive mechanisms. ERS acts through inhibition of the liver-identity (LIVER-ID) transcription factor (TF) network, initiated by rapid LIVER-ID TF protein loss. In addition, induction of the transcriptional repressor NFIL3 further contributes to LIVER-ID gene repression. Alteration to the liver TF repertoire translates into compromised activity of regulatory regions characterized by the densest co-recruitment of LIVER-ID TFs and decommissioning of BRD4 super-enhancers driving hepatic identity. While transient repression of the hepatic molecular identity is an intrinsic part of liver repair, sustained disequilibrium between the ERS and LIVER-ID transcriptional programs is linked to liver dysfunction as shown using mouse models of acute liver injury and livers from deceased human septic patients.

中文翻译：

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内质网应激可积极抑制受损肝脏中的肝分子身份。

肝损伤触发肝转录组的适应性重塑，以修复/再生。我们证明这涉及特别深刻的转录组改变，其中涉及处理内质网应激（ERS）的基因的急性诱导伴随着部分肝的去分化。重要的是，广泛的肝基因下调不能简单地归因于继发于ERS基因诱导的辅因子抑制，而是涉及活性抑制机制的组合。ERS通过抑制肝脏身份（LIVER-ID）转录因子（TF）网络而起作用，该过程由快速的LIVER-ID TF蛋白损失引发。另外，转录阻遏物NFIL3的诱导进一步有助于LIVER-ID基因的阻遏。肝脏TF组成库的改变会转化为调节区的活性受损，其特征是最密集的LIVER-ID TF共同招募和BRD4超级增强剂的退役驱动肝脏特性。肝分子身份的短暂抑制是肝脏修复的内在部分，但ERS和LIVER-ID转录程序之间持续的不平衡与肝功能障碍有关，如使用急性肝损伤的小鼠模型和已故人类败血病患者的肝脏所显示的。