RNA-binding protein SPEN controls hepatocyte maturation via regulating Hnf4α expression during liver development

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.