Systemic Identification of Functionally Conserved Long Noncoding RNA Metabolic Regulators in Human and Mouse Livers

Area of Science:

• Genomics
• Molecular Biology
• Biochemistry

Background:

• Most human long noncoding RNAs (lncRNAs) lack sequence conservation, complicating functional studies and clinical translation.
• This study investigates the hypothesis that nonconserved lncRNAs can share conserved metabolic functions across species, termed functionally conserved lncRNA metabolic regulators (fcLMRs).

Purpose of the Study:

• To identify and characterize fcLMRs between human and mouse livers.
• To elucidate the molecular mechanisms by which fcLMRs regulate gene expression and metabolic processes.
• To explore the therapeutic potential of nonconserved lncRNAs in liver diseases like hepatic steatosis.

Main Methods:

• Developed a sequence-independent strategy to identify putative fcLMRs.
• Performed comparative functional analysis of human and mouse lncRNA pairs (h/mLMRs).
• Investigated the mechanism of action for a specific fcLMR (h/mLMR1) involving PABPC1 interaction and downstream signaling pathways.

Main Results:

• Identified several putative fcLMRs exhibiting similar gene regulatory functions.
• Demonstrated that h/mLMR1 regulates triglyceride levels and lipogenic gene expression in both species.
• Elucidated that h/mLMR1 binds to PABPC1 via structurally similar motifs, inhibiting translation and activating the amino acid-mTOR-SREBP1c pathway.
• Showed that PABPC1-binding motifs fully rescued lncRNA function across species.
• Observed elevated h/mLMR1 expression in hepatic steatosis models.

Conclusions:

• Functionally conserved lncRNA metabolic regulators (fcLMRs) represent a novel and widespread biological phenomenon.
• Mouse models of lncRNA function are valuable for studying human liver pathophysiology.
• The PABPC1-binding motif of hLMR1 is a potential drug target for nonconserved lncRNA-mediated diseases like hepatic steatosis.