Mettl14 Deficiency Promotes Fam32a Expression via m6A Modifications to Facilitate the Hepatocyte G1/S Transition

Area of Science:

• Molecular Biology
• Epigenetics
• Hepatology

Background:

• Mettl14 is vital for the m6A methyltransferase complex, impacting mRNA stability and splicing.
• Reduced Mettl14 expression links to hepatocellular carcinoma and liver regeneration.
• Mechanisms of Mettl14 in hepatocyte cell cycle regulation are not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanisms of Mettl14 in regulating hepatocyte cell cycle progression.
• To investigate the role of m6A modifications in Mettl14-mediated cell cycle control.

Main Methods:

• RNA-sequencing (RNA-Seq) and m6A immunoprecipitation sequencing (MeRIP-Seq) were performed in liver-specific Mettl14 knockout mice.
• Analysis focused on mRNA stability, protein levels, and alternative splicing events.

Main Results:

• Mettl14 deficiency led to stabilization of Fam32a mRNA through m6A modifications, increasing Fam32a protein levels.
• Elevated Fam32a expression was found to accelerate the G1/S transition in hepatocytes.
• This acceleration was linked to modulated Cdkn1a splicing, specifically downregulating its variant 2.

Conclusions:

• A novel m6A-dependent pathway regulating hepatocyte cell cycle progression was uncovered.
• Fam32a plays a previously unrecognized role in promoting the G1/S transition.
• Mettl14's function in liver cell cycle control is mediated, in part, by Fam32a and Cdkn1a splicing.