Transcription Impacts the Efficiency of mRNA Translation via Co-transcriptional N6-adenosine Methylation

Abstract

SummaryTranscription and translation are two main pillars of gene expression. Due to the different timings, spots of action, and mechanisms of regulation, these processes are mainly regarded as distinct and generally uncoupled, despite serving a common purpose. Here, we sought for a possible connection between transcription and translation. Employing an unbiased screen of multiple human promoters, we identified a positive effect of TATA box on translation and a general coupling between mRNA expression and translational efficiency. Using a CRISPR-Cas9-mediated approach, genome-wide analyses, and in vitro experiments, we show that the rate of transcription regulates the efficiency of translation. Furthermore, we demonstrate that m6A modification of mRNAs is co-transcriptional and depends upon the dynamics of the transcribing RNAPII. Suboptimal transcription rates lead to elevated m6A content, which may result in reduced translation. This study uncovers a general and widespread link between transcription and translation that is governed by epigenetic modification of mRNAs.

RNA m6A modification and its function in diseases

“…Minimal differences were noted on the content and the location of m 6 A in cytoplasmic mRNA and chromatin-associated nascent pre-mRNA or nucleoplasmic mRNA at steady-state [16], suggesting that m 6 A methylation occurred co-transcriptionally. This idea was supported by recent studies that METTL3 interacted with chromatin and the transcription machinery [17][18][19].…”

Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them

“…In addition to m 6 A, the less abundant N 1 -methyladenosine (m 1 A), which occurs mainly in structured regions of mRNA 5′ UTRs 160 , and hydroxymethylcytosine (hmrC) in coding regions 161 have been associated with increased translation initiation and elongation, respectively. However, increased co-transcriptional methylation of A to m 6 A in mRNA coding regions during slow transcription 162 as well as disrupted tRNA selection by m 6 A in the CDS 163 was recently shown to result in decreased translation efficiency and elongation dynamics, respectively, of m 6 A-modified mRNAs (FIG. 4b).…”

Rethinking m6A Readers, Writers, and Erasers

“…These data, combined with the fact that the methyltransferase machinery is predominantly located in nuclear speckles (Bokar et al 1997, Ping et al 2014) (sites where transcription and RNA processing can occur), suggest that adenosine methylation is a cotranscriptional process. Recent studies have further supported this idea by showing that METTL3 interacts with chromatin and with the transcription machinery and that m 6 A formation is regulated by the rate of transcription (Knuckles et al 2017, Slobodin et al 2017). Further studies investigating potential interactions between the methyltransferase complex and the transcriptional machinery as well as other mRNA processing factors will likely lead to a better understanding of what drives methylation specificity.…”