Transcription Impacts the Efficiency of mRNA Translation via Co-transcriptional N6-adenosine Methylation
Open accessAbstract
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 m 6 A modification of mRNAs is co-transcriptional and depends upon the dynamics of the transcribing RNAPII. Suboptimal transcription rates lead to elevated m 6 A 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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
A slow RNA Pol II mutant induces an increase in m6A deposition on mRNAs, linked to reduced efficiency of mRNA translation.
“A slow RNA Pol II mutant induces an increase in the level of m6A deposition on mRNAs, and this has been linked to a reduced efficiency of mRNA translation (Slobodin et al, 2017).”
From RNA polymerase II speed: a key player in controlling and adapting transcriptome composition (2021) · cites this paper as Slobodin et al, 2017
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Ultrafast and memory-efficient alignment of short DNA sequences to the human genome.
Langmead, B., Trapnell, C., Pop, M., & Salzberg, S. L. (2009) · Genome Biology · doi:10.1186/gb-2009-10-3-r25 · Cited by 21,849 · see citing works
HTSeq—a Python framework to work with high-throughput sequencing data
Anders, S., Pyl, P. T., & Huber, W. (2015) · Bioinformatics · doi:10.1093/bioinformatics/btu638 · Cited by 21,464 · see citing works
Global quantification of mammalian gene expression control
Schwanhäusser, B., Busse, D., Li, N., Dittmar, G., Schuchhardt, J., Wolf, J., Chen, W., & Selbach, M. (2011) · Nature · doi:10.1038/nature10098 · Cited by 6,566 · cited 2× · see citing works
“Interestingly, similar correlations were noticed in both animal cells and yeast (Schwanhäusser et al., 2011; Weinberg et al., 2016), likely indicating an evolutionarily conserved phenomenon.”
BackgroundTopology of the human and mouse m6A RNA methylomes revealed by m6A-seq
Dominissini, D., Moshitch-Moshkovitz, S., Schwartz, S., Salmon-Divon, M., Ungar, L., Osenberg, S., Cesarkas, K., Jacob-Hirsch, J., Amariglio, N., Kupiec, M., et al. (2012) · Nature · doi:10.1038/nature11112 · Cited by 4,884 · see citing works
N6-methyladenosine-dependent regulation of messenger RNA stability
Wang, X., Lu, Z., Gomez, A., Hon, G. C., Yue, Y., Han, D., Fu, Y., Parisien, M., Dai, Q., Jia, G., et al. (2014) · Nature · doi:10.1038/nature12730 · Cited by 4,558 · cited 1× · see citing works
“Several recent studies have connected m6A to the regulation of splicing (Xiao et al., 2016), translation (Meyer et al., 2015; Wang et al., 2015), and degradation (Wang et al., 2014).”
BackgroundComprehensive Analysis of mRNA Methylation Reveals Enrichment in 3′ UTRs and near Stop Codons
Meyer, K. D., Saletore, Y., Zumbo, P., Elemento, O., Mason, C. E., & Jaffrey, S. R. (2012) · Cell · doi:10.1016/j.cell.2012.05.003 · Cited by 4,223 · see citing works
Genome-Wide Analysis in Vivo of Translation with Nucleotide Resolution Using Ribosome Profiling
Ingolia, N. T., Ghaemmaghami, S., Newman, J. R. S., & Weissman, J. S. (2009) · Science · doi:10.1126/science.1168978 · Cited by 3,853 · see citing works
N6-methyladenosine Modulates Messenger RNA Translation Efficiency
Wang, X., Zhao, B. S., Roundtree, I. A., Lu, Z., Han, D., Ma, H., Weng, X., Chen, K., Shi, H., & He, C. (2015) · Cell · doi:10.1016/j.cell.2015.05.014 · Cited by 3,483 · see citing works
Regulation of Translation Initiation in Eukaryotes: Mechanisms and Biological Targets
Sonenberg, N., & Hinnebusch, A. G. (2009) · Cell · doi:10.1016/j.cell.2009.01.042 · Cited by 3,304 · see citing works
Nuclear m6A Reader YTHDC1 Regulates mRNA Splicing
Xiao, W., Adhikari, S., Dahal, U., Chen, Y.-S., Hao, Y.-J., Sun, B.-F., Sun, H.-Y., Li, A., Ping, X.-L., Lai, W.-Y., et al. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.01.012 · Cited by 2,054 · see citing works
Nascent RNA Sequencing Reveals Widespread Pausing and Divergent Initiation at Human Promoters
Core, L. J., Waterfall, J. J., & Lis, J. T. (2008) · Science · doi:10.1126/science.1162228 · Cited by 1,986 · see citing works
5′ UTR m6A Promotes Cap-Independent Translation
Meyer, K. D., Patil, D. P., Zhou, J. L., Zinoviev, A., Skabkin, M. A., Elemento, O., Pestova, T. V., Qian, S., & Jaffrey, S. R. (2015) · Cell · doi:10.1016/j.cell.2015.10.012 · Cited by 1,812 · see citing works
A unifying model for mTORC1-mediated regulation of mRNA translation
Thoreen, C. C., Chantranupong, L., Keys, H. R., Wang, T., Gray, N. S., & Sabatini, D. M. (2012) · Nature · doi:10.1038/nature11083 · Cited by 1,477 · see citing works
Dynamic m6A mRNA methylation directs translational control of heat shock response
Zhou, J. L., Wan, J., Gao, X., Zhang, X., Jaffrey, S. R., & Qian, S. (2015) · Nature · doi:10.1038/nature15377 · Cited by 1,226 · see citing works
Structural basis of N6-adenosine methylation by the METTL3–METTL14 complex
Wang, X., Feng, J. Q., Xue, Y. C., Guan, Z., Zhang, D., Liu, Z., Gong, Z., Wang, Q., Huang, J. B., Tang, C., et al. (2016) · Nature · doi:10.1038/nature18298 · Cited by 1,218 · see citing works
Getting up to speed with transcription elongation by RNA polymerase II
Jonkers, I., & Lis, J. T. (2015) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3953 · Cited by 876 · see citing works
Regulation of the Adenomatous Polyposis Coli Gene by the miR-135 Family in Colorectal Cancer
Nagel, R., le Sage, C., Diosdado, B., van der Waal, M. S., Vrielink, J. A. F. O., Bolijn, A. S., Meijer, G. A., & Agami, R. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-0951 · Cited by 471 · see citing works
Self-citationNott, A., Hir, H. L., & Moore, M. J. (2004) · Genes & Development · doi:10.1101/gad.1163204 · Cited by 408 · see citing works
Weinberg, D. E., Shah, P., Eichhorn, S. W., Hussmann, J. A., Plotkin, J. B., & Bartel, D. P. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.01.043 · Cited by 392 · see citing works
Functional genetic screens for enhancer elements in the human genome using CRISPR-Cas9
Korkmaz, G., Lopes, R., Ugalde, A. P., Nevedomskaya, E., Han, R., Myacheva, K., Zwart, W. T., Elkon, R., & Agami, R. (2016) · Nature Biotechnology · doi:10.1038/nbt.3450 · Cited by 391 · see citing works
Self-citationPre-mRNA splicing is facilitated by an optimal RNA polymerase II elongation rate
Fong, N., Kim, H., Zhou, Y., Ji, X., Qiu, J., Saldi, T., Diener, K., Jones, K., Fu, X.-D., & Bentley, D. L. (2014) · Genes & Development · doi:10.1101/gad.252106.114 · Cited by 287 · see citing works
The DEAD-Box Protein Dhh1p Couples mRNA Decay and Translation by Monitoring Codon Optimality
Radhakrishnan, A., Chen, Y.-H., Martin, S., Alhusaini, N., Green, R., & Coller, J. (2016) · Cell · doi:10.1016/j.cell.2016.08.053 · Cited by 279 · see citing works
Tumour-specific proline vulnerability uncovered by differential ribosome codon reading
Loayza‐Puch, F., Rooijers, K., Buil, L. C. M., Zijlstra, J., Vrielink, J. A. F. O., Lopes, R., Ugalde, A. P., Breugel, P. C. V., Hofland, I., Wesseling, J., et al. (2016) · Nature · doi:10.1038/nature16982 · Cited by 272 · see citing works
Self-citationN6-methyladenosine in mRNA disrupts tRNA selection and translation-elongation dynamics
Choi, J., Ieong, K.-W., DeMi̇rci̇, H., Chen, J., Petrov, A. N., Prabhakar, A., O’Leary, S. E., Dominissini, D., Rechavi, G., Soltis, S. M., et al. (2016) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.3148 · Cited by 260 · see citing works
How Slow RNA Polymerase II Elongation Favors Alternative Exon Skipping
Dujardin, G., Lafaille, C., de la Mata, M., Marasco, L. E., Muñoz, M. J., Jossic-Corcos, C. L., Corcos, L., & Kornblihtt, A. R. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.03.044 · Cited by 236 · see citing works
Zid, B. M., & O’Shea, E. K. (2014) · Nature · doi:10.1038/nature13578 · Cited by 210 · see citing works
Pausing on Polyribosomes: Make Way for Elongation in Translational Control
Richter, J. D., & Coller, J. M. (2015) · Cell · doi:10.1016/j.cell.2015.09.041 · Cited by 204 · see citing works
RNA Polymerase II Subunits Link Transcription and mRNA Decay to Translation
Harel-Sharvit, L., Eldad, N., Haimovich, G., Barkai, O., Duek, L., & Choder, M. (2010) · Cell · doi:10.1016/j.cell.2010.10.033 · Cited by 194 · see citing works
Expander: from expression microarrays to networks and functions
Ulitsky, I., Maron‐Katz, A., Shavit, S., Sagir, D., Linhart, C., Elkon, R., Tanay, A., Sharan, R., Shiloh, Y., & Ron Shamir, A. (2010) · Nature Protocols · doi:10.1038/nprot.2009.230 · Cited by 194 · see citing works
Self-citationWildeman, A. G., Sassone‐Corsi, P., Grundström, T., Zenke, M., & Chambon, P. (1984) · The EMBO Journal · doi:10.1002/j.1460-2075.1984.tb02269.x · Cited by 183 · see citing works
Léveillé, N., Melo, C. A., Rooijers, K., Díaz-Lagares, A., Melo, S. A., Korkmaz, G., Lopes, R., Moqadam, F. A., Maia, A. R., Wijchers, P. J., et al. (2015) · Nature Communications · doi:10.1038/ncomms7520 · Cited by 183 · see citing works
Self-citationHoernes, T. P., Clementi, N., Faserl, K., Glasner, H., Breuker, K., Lindner, H. H., Hüttenhofer, A., & Erlacher, M. D. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv1182 · Cited by 166 · see citing works
Rojas-Durán, M. F., & Gilbert, W. V. (2012) · RNA · doi:10.1261/rna.035865.112 · Cited by 120 · see citing works
Byrne, B. J., Davis, M., Yamaguchi, J., et al. (1983) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.80.3.721 · Cited by 118 · see citing works
p53 induces transcriptional and translational programs to suppress cell proliferation and growth
Loayza-Puch, F., Drost, J., Rooijers, K., Lopes, R., Elkon, R., & Agami, R. (2013) · Genome Biology · doi:10.1186/gb-2013-14-4-r32 · Cited by 114 · see citing works
Self-citationXiao, H., Friesen, J. D., & Lis, J. T. (1995) · Molecular and Cellular Biology · doi:10.1128/mcb.15.10.5757 · Cited by 111 · see citing works
Elfakess, R., & Dikstein, R. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003094 · Cited by 104 · see citing works
The fate of the messenger is pre-determined: A new model for regulation of gene expression
Haimovich, G., Choder, M., Singer, R. H., & Trcek, T. (2013) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2013.01.004 · Cited by 103 · see citing works
ELAV Links Paused Pol II to Alternative Polyadenylation in the Drosophila Nervous System
Oktaba, K., Zhang, W., Lotz, T. S., Jun, D. J., Lemke, S. B., Ng, S., Esposito, E., Levine, M., & Hilgers, V. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.11.024 · Cited by 92 · see citing works
Qi, S., 戚, 树., Ma, J., 马, 俊., Wang, Z., 王, 震., Guo, L., 郭, 磊., Hou, Y., 侯, 毅., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.748889 · Cited by 86 · see citing works
Tamarkin-Ben-Harush, A., Vasseur, J., Debart, F., Ulitsky, I., & Dikstein, R. (2017) · eLife · doi:10.7554/elife.21907 · Cited by 78 · see citing works
Shimba, S., Bokar, J. A., ROTTMAN, F. M., & Reddy, R. (1995) · Nucleic Acids Research · doi:10.1093/nar/23.13.2421 · Cited by 68 · see citing works
Widespread promoter-mediated coordination of transcription and mRNA degradation
Dori-Bachash, M., Shalem, O., Manor, Y. S., Pilpel, Y., & Tirosh, I. (2012) · Genome biology · doi:10.1186/gb-2012-13-12-r114 · Cited by 45 · see citing works
Tamarkin-Ben-Harush, A., Schechtman, E., & Dikstein, R. (2014) · BMC Genomics · doi:10.1186/1471-2164-15-688 · Cited by 22 · see citing works
Marbach-Bar, N., Ben-Noon, A., Ashkenazi, S., Tamarkin-Ben-Harush, A., Avnit-Sagi, T., WALKER, M. D., & Dikstein, R. (2013) · Nature Communications · doi:10.1038/ncomms3118 · Cited by 14 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them
Leppek, K., Das, R., & Barna, M. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.103 · Cited by 949 · see citing works
m6A facilitates hippocampus-dependent learning and memory through YTHDF1
Shi, H., Zhang, X., Weng, Y.-L., Lu, Z., Liu, Y., Lu, Z., Li, J., Hao, P., Zhang, Y., Zhang, F., et al. (2018) · Nature · doi:10.1038/s41586-018-0666-1 · Cited by 546 · see citing works
The m6A epitranscriptome: transcriptome plasticity in brain development and function
Livneh, I., Moshitch-Moshkovitz, S., Amariglio, N., Rechavi, G., & Dominissini, D. (2020) · Nature Reviews Neuroscience · doi:10.1038/s41583-019-0244-z · Cited by 330 · see citing works
RNA m6A modification and its function in diseases
Tong, J., Flavell, R. A., & Li, H.-B. (2018) · Frontiers of Medicine · doi:10.1007/s11684-018-0654-8 · Cited by 233 · see citing works
RNA polymerase II speed: a key player in controlling and adapting transcriptome composition
Muniz, L., Nicolas, E., & Trouche, D. (2021) · The EMBO Journal · doi:10.15252/embj.2020105740 · Cited by 203 · see citing works
“A slow RNA Pol II mutant induces an increase in the level of m 6 A deposition on mRNAs, and this has been linked to a reduced efficiency of mRNA translation (Slobodin et al , 2017).”
m6A RNA Methylation Controls Neural Development and Is Involved in Human Diseases
Du, K., Zhang, L., Lee, T., & Sun, T. (2019) · Molecular Neurobiology · doi:10.1007/s12035-018-1138-1 · Cited by 153 · see citing works
Structural and molecular mechanisms for the control of eukaryotic 5′–3′ mRNA decay
Mugridge, J. S., Coller, J., & Gross, J. D. (2018) · Nature Structural & Molecular Biology · doi:10.1038/s41594-018-0164-z · Cited by 133 · see citing works
Baek, A., Lee, G.-E., Golconda, S., Rayhan, A., Manganaris, A. A., Chen, S., Tirumuru, N., Yu, H., Kim, S., Kimmel, C., et al. (2024) · Nature Microbiology · doi:10.1038/s41564-024-01638-5 · Cited by 52 · see citing works
Forés-Martos, J., Forte, A., García-Martínez, J., & Pérez-Ortín, J. E. (2021) · Cells · doi:10.3390/cells10020334 · Cited by 8 · see citing works
- Authors
- Slobodin, B., Han, R., Calderone, V., Vrielink, J. A. F. O., Loayza-Puch, F., Elkon, R., & Agami, R.
- Affiliations
- The Netherlands Cancer Institute (NL)
- Tel Aviv University (IL)
- Erasmus MC (NL)
- Corresponding author
- Slobodin, Boris
- Elkon, Ran
- Agami, Reuven
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-04
- Volume
- 169
- Issue
- 2
- Pages
- 326-337.e12
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5388891
- OpenAlex
- W2604637348
- Cited by
- 434
- References
- 45
- Citations by year
- 2026: 19 · 2025: 28 · 2024: 32 · 2023: 59 · 2022: 60 · 2021: 74 · 2020: 48 · 2019: 50 · 2018: 42 · 2017: 22
- FWCI
- 18.20
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion)
- Funders
- enhReg ERC-AdV (322493)
- NWO (NGI 93512001/2012)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- transcription-translation coupling, mRNA translation efficiency, N6-methyladenosine, TATA box, RNA polymerase II, transcription rate, human promoters
- MeSH terms
- Adenosine, Gene Expression Regulation, Humans, Methylation, Peptide Chain Initiation, Translational, RNA Polymerase II, RNA Processing, Post-Transcriptional, RNA, Messenger, Transcription, Genetic, Protein Biosynthesis, TATA Box
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
