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Uncovering extensive post-translation regulation during human cell cycle progression by integrative multi-'omics analysis.

ABSTRACT: BACKGROUND:Analysis of high-throughput multi-'omics interactions across the hierarchy of expression has wide interest in making inferences with regard to biological function and biomarker discovery. Expression levels across different scales are determined by robust synthesis, regulation and degradation processes, and hence transcript (mRNA) measurements made by microarray/RNA-Seq only show modest correlation with corresponding protein levels. RESULTS:In this work we are interested in quantitative modelling of correlation across such gene products. Building on recent work, we develop computational models spanning transcript, translation and protein levels at different stages of the H. sapiens cell cycle. We enhance this analysis by incorporating 25+ sequence-derived features which are likely determinants of cellular protein concentration and quantitatively select for relevant features, producing a vast dataset with thousands of genes. We reveal insights into the complex interplay between expression levels across time, using machine learning methods to highlight outliers with respect to such models as proteins associated with post-translationally regulated modes of action. CONCLUSIONS:We uncover quantitative separation between modified and degraded proteins that have roles in cell cycle regulation, chromatin remodelling and protein catabolism according to Gene Ontology; and highlight the opportunities for providing biological insights in future model systems.

SUBMITTER: Parkes GM

PROVIDER: S-EPMC6820968 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Uncovering extensive post-translation regulation during human cell cycle progression by integrative multi-'omics analysis.

Parkes Gregory M GM Niranjan Mahesan M

BMC bioinformatics 20191029 1

<h4>Background</h4>Analysis of high-throughput multi-'omics interactions across the hierarchy of expression has wide interest in making inferences with regard to biological function and biomarker discovery. Expression levels across different scales are determined by robust synthesis, regulation and degradation processes, and hence transcript (mRNA) measurements made by microarray/RNA-Seq only show modest correlation with corresponding protein levels.<h4>Results</h4>In this work we are interested ...[more]

PMID: 31664894

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Project description:Trypanosoma cruzi is the etiological agent for Chagas disease, a neglected parasitic disease in Latin America. Gene transcription control governs the eukaryotic cell replication but is absent in trypanosomatids; thus, it must be replaced by posttranscriptional regulatory events. We investigated the entrance into the T. cruzi replicative cycle using ribosome profiling and proteomics on G1/S epimastigote cultures synchronized with hydroxyurea. We identified 1,784 translationally regulated genes (change > 2, false-discovery rate [FDR] < 0.05) and 653 differentially expressed proteins (change > 1.5, FDR < 0.05), respectively. A major translational remodeling accompanied by an extensive proteome change is found, while the transcriptome remains largely unperturbed at the replicative entrance of the cell cycle. The differentially expressed genes comprise specific cell cycle processes, confirming previous findings while revealing candidate cell cycle regulators that undergo previously unnoticed translational regulation. Clusters of genes showing a coordinated regulation at translation and protein abundance share related biological functions such as cytoskeleton organization and mitochondrial metabolism; thus, they may represent posttranscriptional regulons. The translatome and proteome of the coregulated clusters change in both coupled and uncoupled directions, suggesting that complex cross talk between the two processes is required to achieve adequate protein levels of different regulons. This is the first simultaneous assessment of the transcriptome, translatome, and proteome of trypanosomatids, which represent a paradigm for the absence of transcriptional control. The findings suggest that gene expression chronology along the T. cruzi cell cycle is controlled mainly by translatome and proteome changes coordinated using different mechanisms for specific gene groups. IMPORTANCE Trypanosoma cruzi is an ancient eukaryotic unicellular parasite causing Chagas disease, a potentially life-threatening illness that affects 6 to 7 million people, mostly in Latin America. The antiparasitic treatments for the disease have incomplete efficacy and adverse reactions; thus, improved drugs are needed. We study the mechanisms governing the replication of the parasite, aiming to find differences with the human host, valuable for the development of parasite-specific antiproliferative drugs. Transcriptional regulation is essential for replication in most eukaryotes, but in trypanosomatids, it must be replaced by subsequent gene regulation steps since they lack transcription initiation control. We identified the genome-wide remodeling of mRNA translation and protein abundance during the entrance to the replicative phase of the cell cycle. We found that translation is strongly regulated, causing variation in protein levels of specific cell cycle processes, representing the first simultaneous study of the translatome and proteome in trypanosomatids.

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Uncovering extensive post-translation regulation during human cell cycle progression by integrative multi-'omics analysis.

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Uncovering extensive post-translation regulation during human cell cycle progression by integrative multi-'omics analysis.

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