Zhang Jiayulin, Yang Ziyan, Yan Xianchun, Duan Juanli, Ruan Bai, Zhang Xiaoyan, Wen Ting, Zhang Peiran, Liang Liang, Han Hua
State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, 710032, China.
State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, 710032, China.
Biochem Biophys Res Commun. 2023 Jan 29;642:128-136. doi: 10.1016/j.bbrc.2022.12.057. Epub 2022 Dec 21.
Liver organogenesis is a complex process. Although many signaling pathways and key factors have been identified during liver development, little is known about the regulation of late liver development, especially liver maturation. As a transcriptional repressor, SPEN has been demonstrated to interact with lncRNAs and transcription factors to participate in X chromosome inactivation, neural development, and lymphocyte differentiation. General disruption of SPEN results in embryonic lethality accompanied by hampered liver development in mice. However, the function of SPEN in embryonic liver development has not been reported. In this study, we demonstrate that SPEN is required for hepatocyte maturation using hepatocyte-specific disruption of SPEN with albumin-Cre-mediated knockout. SPEN expression was upregulated in hepatocytes along with liver development in mice. The deletion of the SPEN gene repressed hepatic maturation, mainly by a decrease in hepatic metabolic function and disruption of hepatocyte zonation. Additional experiments revealed that transcription factors which control hepatocyte maturation were strongly downregulated in SPEN-deficient hepatocytes, especially Hnf4α. Furthermore, restoration of Hnf4α levels partially rescued the immature state of hepatocytes caused by SPEN gene deletion. Taken together, these results reveal an unexpected role of SPEN in liver maturation.
肝脏器官发生是一个复杂的过程。尽管在肝脏发育过程中已经确定了许多信号通路和关键因子，但对于肝脏晚期发育，尤其是肝脏成熟的调控机制却知之甚少。作为一种转录抑制因子，SPEN已被证明可与长链非编码RNA（lncRNAs）和转录因子相互作用，参与X染色体失活、神经发育和淋巴细胞分化。SPEN的全面缺失会导致小鼠胚胎致死，并伴有肝脏发育受阻。然而，SPEN在胚胎肝脏发育中的功能尚未见报道。在本研究中，我们利用白蛋白-Cre介导的基因敲除技术在肝细胞中特异性敲除SPEN，证明了SPEN是肝细胞成熟所必需的。在小鼠肝脏发育过程中，SPEN在肝细胞中的表达上调。SPEN基因的缺失抑制了肝脏成熟，主要表现为肝脏代谢功能下降和肝细胞区域化破坏。进一步的实验表明，在缺乏SPEN的肝细胞中，控制肝细胞成熟的转录因子显著下调，尤其是肝细胞核因子4α（Hnf4α）。此外，恢复Hnf4α水平可部分挽救由SPEN基因缺失导致的肝细胞不成熟状态。综上所述，这些结果揭示了SPEN在肝脏成熟过程中意想不到的作用。
