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m6A-Driver: Identifying Context-Specific mRNA m6A Methylation-Driven Gene Interaction Networks
Song-Yao Zhang1, Shao-Wu Zhang1, Lian Liu1
1School of Automation, Northwestern Polytechnical University, Xi'an, Shaanxi, China.
Abstract:
As the most prevalent mammalian mRNA epigenetic modification, N6-methyladenosine (m6A) has been shown to possess important post-transcriptional regulatory functions. However, the regulatory mechanisms and functional circuits of m6A are still largely elusive. To help unveil the regulatory circuitry mediated by mRNA m6A methylation, we develop here m6A-Driver, an algorithm for predicting m6A-driven genes and associated networks, whose functional interactions are likely to be actively modulated by m6A methylation under a specific condition. Specifically, m6A-Driver integrates the PPI network and the predicted differential m6A methylation sites from methylated RNA immunoprecipitation sequencing (MeRIP-Seq) data using a Random Walk with Restart (RWR) algorithm and then builds a consensus m6A-driven network of m6A-driven genes. To evaluate the performance, we applied m6A-Driver to build the context-specific m6A-driven networks for 4 known m6A (de)methylases, i.e., FTO, METTL3, METTL14 and WTAP. Our results suggest that m6A-Driver can robustly and efficiently identify m6A-driven genes that are functionally more enriched and associated with higher degree of differential expression than differential m6A methylated genes. Pathway analysis of the constructed context-specific m6A-driven gene networks further revealed the regulatory circuitry underlying the dynamic interplays between the methyltransferases and demethylase at the epitranscriptomic layer of gene regulation.
Insights
This study introduces m6A-Driver, a new algorithm to predict genes and networks regulated by N6-methyladenosine (m6A) epigenetic modifications. It helps uncover complex regulatory circuits in gene expression.
Area of Science:
- Molecular Biology
- Epigenetics
- Bioinformatics
Background:
- N6-methyladenosine (m6A) is the most common mRNA epigenetic modification in mammals, crucial for post-transcriptional gene regulation.
- The precise regulatory mechanisms and functional networks of m6A remain largely unclear.
- Understanding m6A's role is vital for deciphering gene regulation at the epitranscriptomic layer.
Purpose of the Study:
- To develop m6A-Driver, an algorithm for predicting m6A-driven genes and their associated regulatory networks.
- To unveil the functional circuits actively modulated by m6A methylation under specific biological conditions.
- To provide insights into the dynamic interplay of m6A regulators.
Main Methods:
- Integration of protein-protein interaction (PPI) networks with predicted differential m6A methylation sites from MeRIP-Seq data.
- Application of the Random Walk with Restart (RWR) algorithm to identify m6A-driven genes.
- Construction of context-specific m6A-driven networks for key m6A regulators (FTO, METTL3, METTL14, WTAP).
Main Results:
- m6A-Driver robustly identifies m6A-driven genes with higher functional enrichment and differential expression compared to genes with differential m6A methylation.
- Successfully constructed context-specific m6A-driven networks for known m6A (de)methylases.
- Demonstrated the algorithm's efficiency in revealing condition-specific regulatory circuitry.
Conclusions:
- m6A-Driver is an effective tool for dissecting m6A-mediated gene regulatory networks.
- The findings illuminate the complex epitranscriptomic regulation driven by m6A.
- Provides a foundation for further research into m6A's role in various biological processes.
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