Splicing regulator SLU7 is essential for maintaining liver homeostasis

Area of Science:

• Hepatology
• Molecular Biology
• Cancer Research

Background:

• Cellular differentiation and proliferation balance is vital for tissue homeostasis, especially in the liver.
• Liver carcinogenesis involves hepatocellular dedifferentiation and uncontrolled proliferation.
• Maintaining hepatocellular identity and quiescence is critical for liver function.

Purpose of the Study:

• To identify key genes regulating hepatocellular homeostasis and identify potential therapeutic targets for liver cancer.
• To investigate the role of SLU7, a pre-mRNA splicing regulator, in maintaining liver cell identity and function.

Main Methods:

• SLU7 knockdown in human liver cells and mouse models.
• Analysis of pre-mRNA splicing and gene expression changes.
• Assessment of metabolic functions and cellular proliferation.

Main Results:

• SLU7 knockdown caused significant alterations in splicing and gene expression, impairing glucose and lipid metabolism.
• Loss of SLU7 led to refractoriness to metabolic hormones and a reversion to a fetal-like gene expression pattern.
• SLU7 depletion increased hepatocellular proliferation and promoted a glycolytic phenotype, characteristic of tumors.

Conclusions:

• SLU7 is a pivotal regulator of hepatocellular homeostasis, identity, and quiescence.
• SLU7 controls the splicing and expression of key differentiation genes like Srsf3 and Hnf4α.
• SLU7 is essential for cAMP-regulated gene transcription and maintaining a differentiated hepatocyte state.