Transcriptional Regulation of WTAP Isoforms by NF-κB Signaling in Human Monocytes.

N6-methyladenosine (m6A) is a dynamic RNA modification that critically modulates gene expression in immune responses. While m6A regulators such as WTAP are implicated in inflammatory and autoimmune diseases, the mechanisms governing their expression during innate immune activation remain unclear. Here, we demonstrate that WTAP expression in human CD14(+) monocytes is upregulated upon lipopolysaccharide (LPS) stimulation and is associated with alternative promoter usage leading to distinct mRNA isoforms. Bioinformatic analysis and pharmacological inhibition reveal that the transcription factor RELA (NF-κB pathway) directly contributes to this promoter-specific induction. Functional analyses show that both WTAP isoforms encode identical proteins, indicating transcriptional, rather than post-transcriptional, regulation. These findings uncover a novel NF-κB-dependent mechanism regulating WTAP isoform expression in activated monocytes, providing insight into the epitranscriptomic modulation of inflammation and potential dysregulation in autoimmune disease.