title: Transcription Impacts the Efficiency of mRNA Translation via Co-transcriptional N6-adenosine Methylation.
abstract: Transcription 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.
authors.affiliation: Division of Oncogenomics, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. Electronic address: boris.slobodin@gmail.com.
authors.forename: Boris
authors.initials: B
authors.lastname: Slobodin
authors.affiliation: Division of Oncogenomics, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Ruiqi
authors.initials: R
authors.lastname: Han
authors.affiliation: Division of Oncogenomics, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Calderone
authors.affiliation: Division of Oncogenomics, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Joachim A F Oude
authors.initials: JAFO
authors.lastname: Vrielink
authors.affiliation: Division of Oncogenomics, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Fabricio
authors.initials: F
authors.lastname: Loayza-Puch
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: ranel@tauex.tau.ac.il.
authors.forename: Ran
authors.initials: R
authors.lastname: Elkon
authors.affiliation: Division of Oncogenomics, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; Department of Genetics, Erasmus University Medical Center, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands. Electronic address: r.agami@nki.nl.
authors.forename: Reuven
authors.initials: R
authors.lastname: Agami
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008745:Methylation; D010442:Peptide Chain Initiation, Translational; D014176:Protein Biosynthesis; D012319:RNA Polymerase II / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism*; D016385:TATA Box; D014158:Transcription, Genetic
chemical_list: D012333:RNA, Messenger; C010223:N-methyladenosine; D012319:RNA Polymerase II; D000241:Adenosine
keywords: N6-adenosine methylation; RNAPII; TATA; gene regulation; m(6)A; transcription; translation efficiency