RNA-binding protein SPEN controls hepatocyte maturation via regulating Hnf4α expression during liver development.
RNA-binding protein SPEN controls hepatocyte maturation via regulating Hnf4α expression during liver development.
复制标题
RNA 结合蛋白 SPEN 通过调节肝脏发育过程中 Hnf4α 的表达来控制肝细胞成熟。
DOI：
10.1016/j.bbrc.2022.12.057
复制
发表时间：
2022-12
期刊：
影响因子：
--
通讯作者：
Han Hua
中科院分区：
文献类型：
--
作者：
Zhang Jia-Yu-Lin;Yang Zi-Yan;Yan Xian-Chun;Duan Juan-Li;Ruan Bai;Zhang Xiao-Yan;Wen Ting;Zhang Pei-Ran;Liang Liang;Han Hua
肝脏器官发生是一个复杂的过程。虽然许多信号通路和关键因素已被确定在肝脏发育过程中，很少有人知道肝脏发育后期的调控，特别是肝脏成熟。SPEN作为一种转录抑制因子，与lncRNA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的一般破坏导致胚胎死亡，伴随着小鼠肝脏发育受阻。但SPEN在胚胎肝发育中的作用尚未见报道。在这项研究中，我们证明了SPEN是肝细胞成熟所必需的，使用白蛋白Cre介导的基因敲除肝细胞特异性破坏SPEN。SPEN表达在小鼠肝细胞中随着肝脏发育沿着上调。SPEN基因的缺失抑制了肝的成熟，主要是通过降低肝代谢功能和破坏肝细胞分区。进一步的实验表明，控制肝细胞成熟的转录因子在SPEN缺陷肝细胞中强烈下调，尤其是Hnf4α。此外，Hnf 4 α水平的恢复部分挽救了由SPEN基因缺失引起的肝细胞的不成熟状态。总之，这些结果揭示了SPEN在肝脏成熟中的意想不到的作用。
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.
登录
查看更多内容
影响因子：
25.7
作者：
Godoy P;Schmidt-Heck W;Natarajan K;Lucendo-Villarin B;Szkolnicka D;Asplund A;Björquist P;Widera A;Stöber R;Campos G;Hammad S;Sachinidis A;Chaudhari U;Damm G;Weiss TS;Nüssler A;Synnergren J;Edlund K;Küppers-Munther B;Hay DC;Hengstler JG
通讯作者：
Hengstler JG
影响因子：
2.9
作者：
Y. Tauran;S. Poulain;M. Lereau-Bernier;Mathieu Danoy;M. Shinohara;B. Ségard;S. Kato;Taketomo Kido;A. Miyajima;Y. Sakai;C. Plessy;E. Leclerc
通讯作者：
Y. Tauran;S. Poulain;M. Lereau-Bernier;Mathieu Danoy;M. Shinohara;B. Ségard;S. Kato;Taketomo Kido;A. Miyajima;Y. Sakai;C. Plessy;E. Leclerc
影响因子：
2.9
作者：
Newberry, EP;Latifi, T;Towler, DA
通讯作者：
Towler, DA
影响因子：
11.4
作者：
Qu, Xiaoling;Lam, Eric;Yang, Yu-Chung
通讯作者：
Yang, Yu-Chung
影响因子：
6
作者：
Wang B;Jakus AE;Baptista PM;Soker S;Soto-Gutierrez A;Abecassis MM;Shah RN;Wertheim JA
通讯作者：
Wertheim JA