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Transcriptome-wide comparison of stress granules and P-bodies reveals that translation plays a major role in RNA partitioning

ABSTRACT: The eukaryotic cytosol contains multiple RNP granules including P-bodies and stress granules. Three different methods have been used to describe the transcriptome of stress granules or P-bodies, but how these methods compare, and how RNA partitioning occurs between P-bodies and stress granules has not been addressed. Herein, we compare the analysis of the stress granule transcriptome based on differential centrifugation, with and without subsequent stress granule immunopurification. We find that while differential centrifugation alone gives a first approximation of the stress granule transcriptome, this methodology contains non-specific transcripts that play a confounding role in the interpretation of results. We also immunopurify and compare the RNAs in stress granules and P-bodies under arsenite stress and compare those results to the P-body transcriptome described under non-stress conditions. We find that the P-body transcriptome is dominated by poorly translated mRNAs under non-stress conditions, but during arsenite stress, when translation is globally repressed, the P-body transcriptome is very similar to the stress granule transcriptome. This suggests that translation is a dominant factor in targeting mRNAs into both P-bodies and stress granules, and during stress, when most mRNAs are untranslated, the composition of P- bodies reflects this broader translation repression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE138988 | GEO | 2019/10/17

REPOSITORIES: GEO

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Project description:During cell stress, the transcription and translation of immediate early genes are prioritized, while most other mRNAs are stored away in stress granules or degraded in P-bodies. TIA-1 is an mRNA binding protein that needs to translocate from the nucleus to seed the formation of stress granules in the cytoplasm. Since other stress granule components such as TDP-43, FUS, ATXN2, SMN, MAPT, HNRNPA2B1 and HNRNPA1 are crucial for the motor neuron diseases ALS / SMA and for the frontotemporal dementia FTD, here we studied mouse nervous tissue to identify mRNAs with selective dependence on Tia1 deletion. Transcriptome profiling with oligonucleotide microarrays in comparison of spinal cord and cerebellum, together with independent validation in quantitative reverse transcriptase PCR and immunoblots demonstrated several strong and consistent dysregulations. In agreement with previously reported TIA1 knock-down effects, cell cycle and apoptosis regulators were affected markedly with expression changes up to 2-fold, exhibiting increased levels for Cdkn1a, Ccnf, and Tprkb versus decreased levels for Bid and Inca1 transcripts. Novel and surprisingly strong expression alterations were detected for fat storage and membrane trafficking factors, with prominent above 3-fold upregulations of Plin4, Wdfy1, Tbc1d24, and Pnpla2, versus a 0.5 -fold?? downregulation of Cntn4 transcript, encoding an axonal membrane adhesion factor with established haploinsufficiency. In comparison subtle effects on the RNA processing machinery included up to 1.2-fold upregulations of Dcp1b and Tial1. The effect on lipid dynamics factors is noteworthy, since also the gene deletion of Tardbp (encoding TDP-43) and Atxn2 led to fat metabolism phenotypes in mouse. In conclusion, genetic ablation of the stress granule nucleator TIA-1 has a novel major effect on mRNAs encoding lipid homeostasis factors in the brain. Factorial design comparing Tia1 knock-out mice with wild type littermates in four different tissues (midbrain, cerebellum, liver, spinal cord) and 2 different ages.

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Transcriptome-wide comparison of stress granules and P-bodies reveals that translation plays a major role in RNA partitioning

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