Dynamic control of chromatin-associated mA methylation regulates nascent RNA synthesis.

N-methyladenosine (mA) methylation is co-transcriptionally deposited on mRNA, but a possible role of mA on transcription remains poorly understood. Here, we demonstrate that the METTL3/METTL14/WTAP mA methyltransferase complex (MTC) is localized to many promoters and enhancers and deposits the mA modification on nascent transcripts, including pre-mRNAs, promoter upstream transcripts (PROMPTs), and enhancer RNAs. PRO-seq analyses demonstrate that nascent RNAs originating from both promoters and enhancers are significantly decreased in the METTL3-depleted cells. Furthermore, genes targeted by the Integrator complex for premature termination are depleted of METTL3, suggesting a potential antagonistic relationship between METTL3 and Integrator. Consistently, we found the Integrator complex component INTS11 elevated at promoters and enhancers upon loss of MTC or nuclear mA binders. Taken together, our findings suggest that MTC-mediated mA modification protects nascent RNAs from Integrator-mediated termination and promotes productive transcription, thus unraveling an unexpected layer of gene regulation imposed by RNA mA modification.