Toward a Genome-Wide Landscape of Translational Control

Larsson, Ola; Tian, Bin; Sonenberg, Nahum

doi:10.1101/cshperspect.a012302

Cited by 53 publications

(58 citation statements)

References 113 publications

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“…Translational control is emerging as a principal posttranscriptional mechanism that can substantially affect protein levels genome wide (27). Although fibrotic tissues and fibroblasts have been mainly studied at the steady-state RNA level (commonly designated the "transcriptome," although mechanisms regulating other regulatory steps such as RNA stability also affect steady-state RNA levels), there is evidence for pathologically regulated mRNA translation in fibrotic fibroblasts (28).…”

Section: Introductionmentioning

confidence: 99%

Fibrotic extracellular matrix activates a profibrotic positive feedback loop

Parker¹,

Rossi²,

Peterson³

et al. 2014

J. Clin. Invest.

471

416

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Pathological remodeling of the extracellular matrix (ECM) by fibroblasts leads to organ failure. Development of idiopathic pulmonary fibrosis (IPF) is characterized by a progressive fibrotic scarring in the lung that ultimately leads to asphyxiation; however, the cascade of events that promote IPF are not well defined. Here, we examined how the interplay between the ECM and fibroblasts affects both the transcriptome and translatome by culturing primary fibroblasts generated from IPF patient lung tissue or nonfibrotic lung tissue on decellularized lung ECM from either IPF or control patients. Surprisingly, the origin of the ECM had a greater impact on gene expression than did cell origin, and differences in translational control were more prominent than alterations in transcriptional regulation. Strikingly, genes that were translationally activated by IPF-derived ECM were enriched for those encoding ECM proteins detected in IPF tissue. We determined that genes encoding IPF-associated ECM proteins are targets for miR-29, which was downregulated in fibroblasts grown on IPF-derived ECM, and baseline expression of ECM targets could be restored by overexpression of miR-29. Our data support a model in which fibroblasts are activated to pathologically remodel the ECM in IPF via a positive feedback loop between fibroblasts and aberrant ECM. Interrupting this loop may be a strategy for IPF treatment.

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Section: Introductionmentioning

confidence: 99%

Fibrotic extracellular matrix activates a profibrotic positive feedback loop

Parker¹,

Rossi²,

Peterson³

et al. 2014

J. Clin. Invest.

471

416

View full text Add to dashboard Cite

show abstract

“…Therefore, it is highly recommended to apply anota analysis for identification of changes in translation on a genome-wide scale. While the theoretical underpinnings of the anota algorithm were discussed in detail previously 21,23,26 , here focus is on how to apply it in practice.…”

Section: Introductionmentioning

confidence: 99%

“…PERK, PKR, HRI and GCN2) inhibit eIF2 by phosphorylating its eIF2α regulatory subunit in response to nutrient deprivation, ERstress and virus infection 6,12 . Therefore, to determine differences in translation using genome-wide data from polysome-associated mRNA it is necessary to correct for the effects from steps in the gene expression pathway that are upstream of translation 21 . To allow such a correction, cytosolic RNA is prepared in parallel with polysome-associated RNA from each sample and the genome-wide steady-state mRNA levels are determined 21 .…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, to determine differences in translation using genome-wide data from polysome-associated mRNA it is necessary to correct for the effects from steps in the gene expression pathway that are upstream of translation 21 . To allow such a correction, cytosolic RNA is prepared in parallel with polysome-associated RNA from each sample and the genome-wide steady-state mRNA levels are determined 21 . Currently, so-called "translation-efficiency" (TE) scores (i.e.…”

Section: Introductionmentioning

confidence: 99%

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Polysome Fractionation and Analysis of Mammalian Translatomes on a Genome-wide Scale

Gandin

Sikström

Alain

et al. 2014

JoVE

168

153

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AbstractmRNA translation plays a central role in the regulation of gene expression and represents the most energy consuming process in mammalian cells. Accordingly, dysregulation of mRNA translation is considered to play a major role in a variety of pathological states including cancer. Ribosomes also host chaperones, which facilitate folding of nascent polypeptides, thereby modulating function and stability of newly synthesized polypeptides. In addition, emerging data indicate that ribosomes serve as a platform for a repertoire of signaling molecules, which are implicated in a variety of post-translational modifications of newly synthesized polypeptides as they emerge from the ribosome, and/or components of translational machinery. Herein, a well-established method of ribosome fractionation using sucrose density gradient centrifugation is described. In conjunction with the in-house developed "anota" algorithm this method allows direct determination of differential translation of individual mRNAs on a genome-wide scale. Moreover, this versatile protocol can be used for a variety of biochemical studies aiming to dissect the function of ribosome-associated protein complexes, including those that play a central role in folding and degradation of newly synthesized polypeptides.

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“…Measurements based on quantitative reverse transcription-PCR assessing the mRNA, although improving the sensitivity considerably, presents an obvious disadvantage of quantifying the enzyme indirectly [9]. Additionally, cellular regulations between the mRNA and the enzyme may scramble the correlations between mRNA and enzyme levels [10]. Perhaps more importantly, the currently available methods measure the amount rather than activities or functionalities of enzymes.…”

Section: Why Dna-modifying Enzymes?mentioning

confidence: 99%