Super-enhancer RNA mA promotes local chromatin accessibility and oncogene transcription in pancreatic ductal adenocarcinoma.

The biological functions of noncoding RNA N-methyladenosine (mA) modification remain poorly understood. In the present study, we depict the landscape of super-enhancer RNA (seRNA) mA modification in pancreatic ductal adenocarcinoma (PDAC) and reveal a regulatory axis of mA seRNA, H3K4me3 modification, chromatin accessibility and oncogene transcription. We demonstrate the cofilin family protein CFL1, overexpressed in PDAC, as a METTL3 cofactor that helps seRNA mA methylation formation. The increased seRNA mAs are recognized by the reader YTHDC2, which recruits H3K4 methyltransferase MLL1 to promote H3K4me3 modification cotranscriptionally. Super-enhancers with a high level of H3K4me3 augment chromatin accessibility and facilitate oncogene transcription. Collectively, these results shed light on a CFL1-METTL3-seRNA mA-YTHDC2/MLL1 axis that plays a role in the epigenetic regulation of local chromatin state and gene expression, which strengthens our knowledge about the functions of super-enhancers and their transcripts.