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A regression-based analysis of ribosome-profiling data reveals a conserved complexity to mammalian translation

ABSTRACT: A fundamental goal of genomics is to identify the complete set of expressed proteins. Automated annotation strategies rely on assumptions about protein-coding sequences (CDSs), e.g., they are conserved, do not overlap, and exceed a minimum length. However, an increasing number of newly discovered proteins violate these rules. Here we present an experimental and analytical framework, based on ribosome profiling and linear regression, for systematic identification and quantification of translation. Application of this approach to lipopolysaccharide-stimulated mouse dendritic cells and HCMV-infected human fibroblasts identifies thousands of novel CDSs, including micropeptides and variants of known proteins, that bear the hallmarks of canonical translation and exhibit comparable translation levels and dynamics to annotated CDSs. Remarkably, many translation events are identified in both mouse and human cells even when the peptide sequence is not conserved. Our work thus reveals an unexpected complexity to mammalian translation suited to provide both conserved regulatory or protein-based functions.

ORGANISM(S): Mus musculus

PROVIDER: GSE74139 | GEO | 2015/12/03

SECONDARY ACCESSION(S): PRJNA299160

REPOSITORIES: GEO

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A regression-based analysis of ribosome-profiling data reveals a conserved complexity to mammalian translation

Project description:A fundamental goal of genomics is to identify the complete set of expressed proteins. Automated annotation strategies rely on assumptions about protein-coding sequences (CDSs), e.g., they are conserved, do not overlap, and exceed a minimum length. However, an increasing number of newly discovered proteins violate these rules. Here we present an experimental and analytical framework, based on ribosome profiling and linear regression, for systematic identification and quantification of translation. Application of this approach to lipopolysaccharide-stimulated mouse dendritic cells and HCMV-infected human fibroblasts identifies thousands of novel CDSs, including micropeptides and variants of known proteins, that bear the hallmarks of canonical translation and exhibit comparable translation levels and dynamics to annotated CDSs. Remarkably, many translation events are identified in both mouse and human cells even when the peptide sequence is not conserved. Our work thus reveals an unexpected complexity to mammalian translation suited to provide both conserved regulatory or protein-based functions. 37 ribosome footprint samples from mouse BMDCs across a time course of LPS stimulation and in the presence or absence of translation inhibitors cycloheximide, harringtonine, or lactimidomycin. A mock (non-LPS stimulated) time course is also included, collected in the presence of cycloheximide. Two replicates are available for the LPS timecourse under CHX treatment.

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A regression-based analysis of ribosome-profiling data reveals a conserved complexity to mammalian translation

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Ribosome profiling of dhh1∆ yeast

Project description:The impact of RNA structures in coding sequences (CDS) within mRNAs is poorly understood. Here  we identify a novel and highly conserved mechanism of translational control involving RNA structures within coding sequences and the DEAD-box helicase Dhh1. Using yeast genetics and  genome-wide ribosome profiling analyses we show that this mechanism, initially derived from studies  of the Brome Mosaic virus RNA genome, extends to yeast and human mRNAs highly enriched in  membrane and secreted proteins. All Dhh1-dependent mRNAs, viral and cellular, share key common  features. First, they contain long and highly structured CDSs, including a region located around 42 to  120 nucleotides after the translation initiation site, second, they are directly bound by Dhh1 with a  specific binding distribution and third, complementary experimental approaches suggest that they are  activated by Dhh1 at the translation initiation step. Our results show that ribosome translocation is not the only unwinding force of CDS and uncover a conserved layer of translational control that involve  RNA helicases and RNA folding within CDS providing novel opportunities for regulation of  membrane and secretome proteins.

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