Slu7 is essential for liver differentiation, metabolism and quiescence

The equilibrium between cellular differentiation and proliferation is fundamental for tissue homeostasis. This is particularly important for the liver, a highly differentiated organ with systemic metabolic functions still endowed with unparalleled regenerative potential. Hepatocellular de-differentiation and uncontrolled proliferation are at the basis of liver carcinogenesis. We have identified SLU7, a pre-mRNA splicing regulator inhibited in hepatocarcinoma as a pivotal gene for hepatocellular homeostasis. SLU7 knockdown in human liver cells and mouse liver resulted in profound changes in pre-mRNA splicing and gene expression, leading to impaired glucose and lipid metabolism, refractoriness to key metabolic hormones, and reversion to a fetal-like gene expression pattern. Hepatocellular proliferation and a switch to a tumor-like glycolytic phenotype were also observed. Mechanistically, SLU7 governed the splicing and/or expression of essential genes for hepatocellular differentiation like SRSF3 and HNF4a, and was identified as a critical factor in cAMP-regulated gene transcription. SLU7 is therefore central for hepatocyte identity and quiescence. The expression of the splicing factor SLU7 in the human hepatocellular carcinoma cell line PLC/PRF/5 was knocked down with specific siRNAs (siSlu7). An irrelevant siRNA (siGL2) was used as negative control. The RNAto perfrom the array analysis was extracted 48h after transfection.