Dataset Information

The genetic and biochemical determinants of mRNA degradation rates in mammals.

ABSTRACT:

Background

Degradation rate is a fundamental aspect of mRNA metabolism, and the factors governing it remain poorly characterized. Understanding the genetic and biochemical determinants of mRNA half-life would enable more precise identification of variants that perturb gene expression through post-transcriptional gene regulatory mechanisms.

Results

We establish a compendium of 39 human and 27 mouse transcriptome-wide mRNA decay rate datasets. A meta-analysis of these data identified a prevalence of technical noise and measurement bias, induced partially by the underlying experimental strategy. Correcting for these biases allowed us to derive more precise, consensus measurements of half-life which exhibit enhanced consistency between species. We trained substantially improved statistical models based upon genetic and biochemical features to better predict half-life and characterize the factors molding it. Our state-of-the-art model, Saluki, is a hybrid convolutional and recurrent deep neural network which relies only upon an mRNA sequence annotated with coding frame and splice sites to predict half-life (r=0.77). The key novel principle learned by Saluki is that the spatial positioning of splice sites, codons, and RNA-binding motifs within an mRNA is strongly associated with mRNA half-life. Saluki predicts the impact of RNA sequences and genetic mutations therein on mRNA stability, in agreement with functional measurements derived from massively parallel reporter assays.

Conclusions

Our work produces a more robust ground truth for transcriptome-wide mRNA half-lives in mammalian cells. Using these revised measurements, we trained Saluki, a model that is over 50% more accurate in predicting half-life from sequence than existing models. Saluki succinctly captures many of the known determinants of mRNA half-life and can be rapidly deployed to predict the functional consequences of arbitrary mutations in the transcriptome.

SUBMITTER: Agarwal V

PROVIDER: S-EPMC9684954 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Publications

The genetic and biochemical determinants of mRNA degradation rates in mammals.

Agarwal Vikram V Kelley David R DR

Genome biology 20221123 1

<h4>Background</h4>Degradation rate is a fundamental aspect of mRNA metabolism, and the factors governing it remain poorly characterized. Understanding the genetic and biochemical determinants of mRNA half-life would enable more precise identification of variants that perturb gene expression through post-transcriptional gene regulatory mechanisms.<h4>Results</h4>We establish a compendium of 39 human and 27 mouse transcriptome-wide mRNA decay rate datasets. A meta-analysis of these data identifie ...[more]

PMID: 36419176

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Project description:Buprofezin is a widely used insect growth regulator whose residue has been frequently detected in the environment, posing a threat to aquatic organisms and nontarget insects. Microorganisms play an important role in the degradation of buprofezin in the natural environment. However, the relevant catabolic pathway has not been fully characterized, and the molecular mechanism of catabolism is still completely unknown. Rhodococcus qingshengii YL-1 can utilize buprofezin as a sole source of carbon and energy for growth. In this study, the upstream catabolic pathway in strain YL-1 was identified using tandem mass spectrometry. Buprofezin is composed of a benzene ring and a heterocyclic ring. The degradation is initiated by the dihydroxylation of the benzene ring and continues via dehydrogenation, aromatic ring cleavage, breaking of an amide bond, and the release of the heterocyclic ring 2-tert-butylimino-3-isopropyl-1,3,5-thiadiazinan-4-one (2-BI). A buprofezin degradation-deficient mutant strain YL-0 was isolated. A comparative genomic analysis combined with gene deletion and complementation experiments revealed that the gene cluster bfzBA3A4A1A2C is responsible for the upstream catabolic pathway of buprofezin. The bfzA3A4A1A2 cluster encodes a novel Rieske nonheme iron oxygenase (RHO) system that is responsible for the dihydroxylation of buprofezin at the benzene ring; bfzB is involved in dehydrogenation, and bfzC is in charge of benzene ring cleavage. Furthermore, the products of bfzBA3A4A1A2C can also catalyze dihydroxylation, dehydrogenation, and aromatic ring cleavage of biphenyl, flavanone, flavone, and bifenthrin. In addition, a transcriptional study revealed that bfzBA3A4A1A2C is organized in one transcriptional unit that is constitutively expressed in strain YL-1.IMPORTANCE There is an increasing concern about the residue and environmental fate of buprofezin. Microbial metabolism is an important mechanism responsible for the buprofezin degradation in the natural environment. However, the molecular mechanism and genetic determinants of microbial degradation of buprofezin have not been well identified. This work revealed that gene cluster bfzBA3A4A1A2C is responsible for the upstream catabolic pathway of buprofezin in Rhodococcus qingshengii YL-1. The products of bfzBA3A4A1A2C could also degrade bifenthrin, a widely used pyrethroid insecticide. These findings enhance our understanding of the microbial degradation mechanism of buprofezin and benefit the application of strain YL-1 and bfzBA3A4A1A2C in the bioremediation of buprofezin contamination.

Dataset Information

The genetic and biochemical determinants of mRNA degradation rates in mammals.

Background

Results

Conclusions

Publications

The genetic and biochemical determinants of mRNA degradation rates in mammals.

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