Conserved long noncoding RNA TILAM promotes liver fibrosis through interaction with PML in HSCs

Area of Science:

• Hepatology and Molecular Biology
• RNA Biology
• Fibrosis Research

Background:

• Liver fibrosis, a common endpoint of chronic liver injury, progresses to end-stage liver disease.
• Hepatic stellate cell (HSC) activation and myofibroblast differentiation drive fibrotic scar formation.
• Long noncoding RNAs (lncRNAs) are emerging regulators of HSC activity and potential therapeutic targets for fibrosis.

Purpose of the Study:

• To identify and characterize novel lncRNAs involved in liver fibrosis.
• To investigate the role of lncRNA TILAM in HSC activation and fibrogenesis.
• To explore TILAM as a potential therapeutic target for liver fibrosis.

Main Methods:

• Identification of TILAM in human and mouse HSCs during liver fibrosis.
• Loss-of-function studies in human HSCs and liver organoids.
• Generation and analysis of Tilam-deficient reporter mice in two liver fibrosis models.
• Investigation of TILAM's interaction with promyelocytic leukemia nuclear body scaffold protein and TGF-β2 signaling.

Main Results:

• TILAM is a lncRNA expressed in HSCs and induced during liver fibrosis in humans and mice.
• TILAM regulates COL1A1 and other extracellular matrix gene expression.
• Loss of TILAM expression attenuated liver fibrosis development in vivo.
• TILAM interacts with promyelocytic leukemia nuclear body scaffold protein, forming a feedback loop with TGF-β2 to enhance HSC fibrotic activity.

Conclusions:

• TILAM is activated in HSCs during liver injury and promotes fibrosis.
• TILAM's interaction with promyelocytic leukemia nuclear body scaffold protein is crucial for fibrotic progression.
• Targeting TILAM offers a potential therapeutic strategy against liver fibrosis and end-stage liver disease.