Deng Yun, Han Xiao, Chen Huiqiao, Zhao Chaoxian, Chen Yi, Zhou Jun, de The Hugues, Zhu Jun, Yuan Hao
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
CNRS-LIA Hematology and Cancer, Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
J Mol Cell Biol. 2023 Aug 3;15(3). doi: 10.1093/jmcb/mjad019.
YPEL5 is a member of the Yippee-like (YPEL) gene family that is evolutionarily conserved in eukaryotic species. To date, the physiological function of YPEL5 has not been assessed due to a paucity of genetic animal models. Here, using CRISPR/Cas9-mediated genome editing, we generated a stable ypel5-/- mutant zebrafish line. Disruption of ypel5 expression leads to liver enlargement associated with hepatic cell proliferation. Meanwhile, hepatic metabolism and function are dysregulated in ypel5-/- mutant zebrafish, as revealed by metabolomic and transcriptomic analyses. Mechanistically, Hnf4a is identified as a crucial downstream mediator that is positively regulated by Ypel5. Zebrafish hnf4a overexpression could largely rescue ypel5 deficiency-induced hepatic defects. Furthermore, PPARα signaling mediates the regulation of Hnf4a by Ypel5 through directly binding to the transcriptional enhancer of the Hnf4a gene. Herein, this work demonstrates an essential role of Ypel5 in hepatocyte proliferation and function and provides the first in vivo evidence for a physiological role of the ypel5 gene in vertebrates.
YPEL5是Yippee样（YPEL）基因家族的成员，该家族在真核生物物种中具有进化保守性。迄今为止，由于缺乏基因动物模型，YPEL5的生理功能尚未得到评估。在此，我们利用CRISPR/Cas9介导的基因组编辑技术，构建了稳定的ypel5基因敲除（ypel5-/-）斑马鱼品系。ypel5表达的破坏导致与肝细胞增殖相关的肝脏肿大。同时，代谢组学和转录组学分析表明，ypel5-/-突变斑马鱼的肝脏代谢和功能失调。从机制上讲，Hnf4a被确定为一个关键的下游介质，受Ypel5正向调控。斑马鱼hnf4a的过表达在很大程度上可以挽救ypel5缺陷诱导的肝脏缺陷。此外，PPARα信号通路通过直接结合Hnf4a基因的转录增强子来介导Ypel5对Hnf4a的调控。在此，这项工作证明了Ypel5在肝细胞增殖和功能中的重要作用，并为ypel5基因在脊椎动物中的生理作用提供了首个体内证据。
