Identification and characterization of methylation-mediated transcriptional dysregulation dictate methylation roles in preeclampsia

Abstract

BACKGROUND: Preeclampsia (PE) is a heterogeneous, hypertensive disorder of pregnancy, with no robust biomarkers or effective treatments. PE increases the risk of poor outcomes for both the mother and the baby. Methylation-mediated transcriptional dysregulation motifs (methTDMs) could contribute the PE development. However, precise functional roles of methTDMs in PE have not been globally described. METHODS: Here, we develop a comprehensive and computational pipeline to identify PE-specific methTDMs following TF, gene, methylation expression profile, and experimentally verified TF-gene interactions. RESULTS: The regulation patterns of methTDMs are multiple and complex in PE and contain relax inhibition, intensify inhibition, relax activation, intensify activation, reverse activation, and reverse inhibition. A core module is extracted from global methTDM network to further depict the mechanism of methTDMs in PE. The common and specific features of any two kinds of regulation pattern are also analyzed in PE. Some key methylation sites, TFs, and genes such as IL2RG are identified in PE. Functional analysis shows that methTDMs are associated with immune-, insulin-, and NK cell-related functions. Drug-related network identifies some key drug repurposing candidates such as NADH. CONCLUSION: Collectively, the study highlighted the effect of methylation on the transcription process in PE. MethTDMs could contribute to identify specific biomarkers and drug repurposing candidates for PE.