Dynamic control of chromatin-associated m⁶A methylation regulates nascent RNA synthesis.

ABSTRACT: N⁶-methyladenosine (m⁶A) methylation is co-transcriptionally deposited on mRNA, but a possible role of m⁶A on transcription remains poorly understood. Here, we demonstrate that the METTL3/METTL14/WTAP m⁶A methyltransferase complex (MTC) is localized to many promoters and enhancers and deposits the m⁶A 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 m⁶A binders. Taken together, our findings suggest that MTC-mediated m⁶A modification protects nascent RNAs from Integrator-mediated termination and promotes productive transcription, thus unraveling an unexpected layer of gene regulation imposed by RNA m⁶A modification.

SUBMITTER: Xu W 

PROVIDER: S-EPMC8969783 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature