Integrative network analysis identifies cell-specific trans regulators of m6A

Area of Science:

• Epigenetics and RNA Biology
• Computational Biology and Bioinformatics

Background:

• N6-methyladenosine (m6A) is a crucial, dynamic RNA modification in eukaryotes.
• Mechanisms establishing cell-specific m6A methylomes remain largely unknown.

Purpose of the Study:

• To develop a computational framework for identifying cell-specific RNA-binding protein (RBP) regulators of m6A.
• To elucidate the trans-acting regulatory mechanisms governing m6A methylome dynamics.

Main Methods:

• Integrated gene expression, RBP binding targets, and motifs with m6A co-methylation networks across diverse cell states.
• Developed a computational framework to systematically identify m6A regulators.
• Validated identified regulators through knockdown experiments and RNA-binding assays.

Main Results:

• Identified 32 high-confidence m6A regulators that modulate m6A sites near stop codons in a cell-specific manner.
• Demonstrated that TRA2A and CAPRIN1 physically interact with m6A writers to promote methylation at specific RNA sites.
• Knockdown of TRA2A increased RNA stability and decreased cell viability.

Conclusions:

• The developed computational framework is a powerful strategy for discovering cell-specific m6A regulators.
• Pervasive trans-acting regulation of m6A provides novel insights into methylome dynamics.
• Identified key RBPs involved in establishing cell-specific m6A patterns.