Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Sequence selectivity of macrolide-induced translational regulation

ABSTRACT: We sequenced a total of 12 cDNA libararies derived from fragmented total mRNA and ribosome protected mRNAs from azithromycin-treated and -untreated S. aureus samples. The data represented 2 independent biological replicates. Examination of the impact of azithromycin on global translatome, mRNA abundance and the ribosome density along the transcripts.

ORGANISM(S): Staphylococcus aureus subsp. aureus NCTC 8325

SUBMITTER: Mee-Ngan Yap

PROVIDER: E-GEOD-57175 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Sequence selectivity of macrolide-induced translational attenuation.

Davis Amber R AR Gohara David W DW Yap Mee-Ngan F MN

Proceedings of the National Academy of Sciences of the United States of America 20141013 43

The prevailing "plug-in-the-bottle" model suggests that macrolide antibiotics inhibit translation by binding inside the ribosome tunnel and indiscriminately arresting the elongation of every nascent polypeptide after the synthesis of six to eight amino acids. To test this model, we performed a genome-wide analysis of translation in azithromycin-treated Staphylococcus aureus. In contrast to earlier predictions, we found that the macrolide does not preferentially induce ribosome stalling near the ...[more]

PMID: 25313041

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Project description:Disruptions of protein homeostasis in the endoplasmic reticulum (ER) elicit activation of the unfolded protein response (UPR), a translation- and transcription-coupled proteostatic stress response pathway. The primary translational control arm of the UPR is initiated by the PERK-dependent phosphorylation of eIF2Î±, leading to a large-scale reprogramming of translation and subsequent activation of an ATF4-mediated transcriptional program. It has remained challenging, however, to accurately evaluate the contribution of each component of the eIF2Î±/ATF4 pathway to the remodelling of transcription and translation. Here, we have used mouse embryonic fibroblasts containing either a knock-in of the non-phosphorylatable eIF2Î± S51A mutant or knock-out for ATF4 by ribosome profiling and mRNA-seq to define the specific contributions of eIF2Î± phosphoryation and ATF4 in controlling the translational and transcriptional components of the UPR. These studies show that the transcriptional and translational targets of each P-eIF2Î±, ATF4, and the other UPR gene expression programs overlapped extensively, leading to a core set of UPR genes whose robust expression in response to ER stress is driven by multiple mechanisms. The identification of other, more factor-specific targets illustrated the potential for functional specialization of the UPR. As the UPR progressed temporally, cells employed distinct combinations of transcriptional and translational mechanisms, initiated by different factors, to adapt to ongoing stress. These effects were accompanied by a buffering effect where changes in mRNA levels were coupled to opposing changes in ribosome loading, a property which makes cooperation between transcription and translation essential to confer robust protein expression. Translational analysis by ribosome profiling and mRNA-seq of PERK pathways mutants during the UPR. Mouse embryonic fibroblasts (MEFs) lacking components of the PERK pathway (eIF2a phosphorylation and ATF4) were subjected to ER stress and analyzed by ribosome profiling.

Dataset Information

Sequence selectivity of macrolide-induced translational regulation

Publications

Sequence selectivity of macrolide-induced translational attenuation.

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