m⁶ A deposition is regulated by PRMT1-mediated arginine methylation of METTL14 in its disordered C-terminal region

Area of Science:

• Molecular Biology
• RNA Biology
• Epigenetics

Background:

• N6-methyladenosine (m⁶ A) is a critical RNA modification involved in RNA metabolism.
• The precise regulatory mechanisms governing m⁶ A deposition remain incompletely understood.

Purpose of the Study:

• To investigate the role of arginine methylation in regulating m⁶ A modification.
• To identify the specific protein arginine methyltransferase involved and its mechanism of action on METTL14.

Main Methods:

• Utilized biochemical assays to demonstrate the interaction and methylation of METTL14 by PRMT1.
• Employed mouse embryonic stem cells (mESCs) with modified METTL14 to assess global m⁶ A levels.
• Performed transcriptome-wide m⁶ A profiling to identify methylation-dependent sites.

Main Results:

• Established protein arginine methyltransferase 1 (PRMT1) methylates the C terminus of METTL14, enhancing its RNA binding and methylation activity.
• METTL14 arginine methylation is crucial for interaction with RNA polymerase II (RNAPII).
• mESCs lacking METTL14 arginine methylation showed reduced global m⁶ A levels and hypersensitivity to DNA crosslinking agents.

Conclusions:

• Arginine methylation of METTL14 is a novel regulatory pathway for m⁶ A deposition in mammalian cells.
• METTL14 arginine methylation influences the expression of genes involved in DNA repair and stem cell maintenance.
• This study uncovers new functions of arginine methylation in RNA metabolism and m⁶ A regulation.