YPEL5是在真核生物中进化保守的YPEL基因家族的成员。迄今为止,由于缺乏遗传动物模型,尚未评估YPEL5的生理功能。这里,使用CRISPR/Cas9介导的基因组编辑,我们产生了稳定的ypel5-/-突变斑马鱼系。ypel5表达的中断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显示,ypel5-/-突变体的肝代谢和功能也失调。机械上,Hnf4a被鉴定为关键的下游介质,并由Ypel5正向调节。Hnf4a过表达可以在很大程度上挽救ypel5缺陷引起的肝缺陷。Further,PPARα信号通过直接结合Hnf4a基因的转录增强子介导Ypel5对Hnf4a的调控。在这里,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第一个体内证据。
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.