System-wide identification and regulatory network analysis of m⁶A-APA associated genes in Arabidopsis Thaliana

N⁶-methyladenosine (m⁶A) modification and alternative polyadenylation (APA) are key post-transcriptional regulatory mechanisms that govern plant growth, development, and stress responses. Although emerging evidence suggests crosstalk between m⁶A and APA in plants, their system-level coordinated regulatory network remains poorly understood. Here, we established an integrated bioinformatics framework to systematically characterize the potential interplay between m⁶A and APA. This framework combines multi-sample correlation analysis of m⁶A modification levels and APA usages, along with random walk with restart (RWR) algorithm-based screening in protein–protein interaction (PPI) networks, to identify candidate genes with inferred m⁶A-APA association (called m6APAreg genes). We collected 56 methylated RNA immunoprecipitation sequencing (MeRIP-seq) datasets under diverse genetic backgrounds and stress conditions in Arabidopsis , and identified 2,505 m6APAreg genes using this integrated bioinformatics framework. Functional enrichment analysis revealed that these genes are significantly enriched in pathways related to metabolism, stress response, and developmental regulation. Orthogonal support from published datasets indicated a higher binding rate of the m⁶A reader CPSF30-L to m6APAreg genes, supported by stronger poly(A) signals. To further explore the potential regulatory hierarchy, we constructed multi-layered regulatory networks integrating m6APAreg genes, miRNAs, transcription factors, and poly(A) factors. Moreover, sample-specific analysis characterized condition-dependent correlation patterns, with the inferred regulatory direction and functional modules of the m⁶A-APA axis dynamically changing in response to genetic background and environmental stress. This study represents the first systematic attempt to prioritize candidate genes associated with the m⁶A-APA regulatory module in Arabidopsis . Our work provides novel insights into the potential complex interplay between epitranscriptomic regulation and 3′ end processing in plants. The established analytical framework and the reservoir of candidate m6APAreg genes offer a valuable resource for future functional validation studies focused on plant development, stress responses, and crop improvement.