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NanoCAGE in ERα knockdown BM67 cells

ABSTRACT: Estrogen receptor alpha (ERα) activity is associated with increased cancer cell proliferation. Studies aiming to understand the impact of ERα on cancer-associated phenotypes have largely been limited to its transcriptional activity. Herein, we demonstrate that ERα coordinates its transcriptional output with selective modulation of mRNA translation. Importantly, translational perturbations caused by depletion of ERα largely manifest as "translational offsetting" of the transcriptome, whereby amounts of translated mRNAs and corresponding protein levels are maintained constant despite changes in mRNA abundance. Transcripts whose levels, but not polysome-association, are reduced following ERα depletion lack features which limit translation efficiency including structured 5'UTRs and miRNA target sites. In contrast, mRNAs induced upon ERα depletion whose polysome-association remains unaltered are enriched in codons requiring U34-modified tRNAs for efficient decoding. Consistently, ERα regulates levels of U34-modifying enzymes and thereby controls levels of U34-modified tRNAs. These findings unravel a hitherto unprecedented mechanism of ERα-dependent orchestration of transcriptional and translational programs that may be a pervasive mechanism of proteome maintenance in hormone-dependent cancers.

ORGANISM(S): Mus musculus

PROVIDER: GSE120916 | GEO | 2019/09/24

REPOSITORIES: GEO

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Polysome profiling quantified by RNA sequencing in ERα knockdown and control BM67 cells

Project description:Estrogen receptor alpha (ERα) activity is associated with increased cancer cell proliferation. Studies aiming to understand the impact of ERα on cancer-associated phenotypes have largely been limited to its transcriptional activity. Herein, we demonstrate that ERα coordinates its transcriptional output with selective modulation of mRNA translation. Importantly, translational perturbations caused by depletion of ERα largely manifest as "translational offsetting" of the transcriptome, whereby amounts of translated mRNAs and corresponding protein levels are maintained constant despite changes in mRNA abundance. Transcripts whose levels, but not polysome-association, are reduced following ERα depletion lack features which limit translation efficiency including structured 5'UTRs and miRNA target sites. In contrast, mRNAs induced upon ERα depletion whose polysome-association remains unaltered are enriched in codons requiring U34-modified tRNAs for efficient decoding. Consistently, ERα regulates levels of U34-modifying enzymes and thereby controls levels of U34-modified tRNAs. These findings unravel a hitherto unprecedented mechanism of ERα-dependent orchestration of transcriptional and translational programs that may be a pervasive mechanism of proteome maintenance in hormone-dependent cancers.

2019-09-24 | GSE134606 | GEO

Small RNA sequencing in ERα knockdown and control BM67 cells

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Polysome profiling quantified by DNA-microarrays in ERα knockdown and control BM67 cells

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Optimization of codon translation rates via tRNA modifications maintains proteome integrity

Project description:Proteins begin to fold as they emerge from translating ribosomes. The kinetics of ribosome transit along a given mRNA can influence nascent chain folding, but the extent to which individual codon translation rates impact proteome integrity remains unknown. Here, we show that slower decoding of discrete codons elicits widespread protein aggregation in vivo. Using ribosome profiling, we find that loss of anticodon wobble uridine (U34) modifications in a subset of tRNAs leads to ribosome pausing at their cognate codons in S. cerevisiae and C. elegans. Yeast cells lacking U34 modifications exhibit gene expression hallmarks of proteotoxic stress and accumulate aggregates of endogenous proteins with key cellular functions. Moreover, these cells are severely compromised in clearing stress-induced protein aggregates. Overexpression of hypomodified tRNAs alleviates ribosome pausing, concomitantly restoring protein homeostasis. Our findings demonstrate that modified U34 is an evolutionarily conserved accelerator of decoding and reveal an unanticipated role for tRNA anticodon modifications in maintaining proteome integrity.

2015-06-04 | GSE67387 | GEO

Optimization of codon translation rates via tRNA modifications maintains proteome integrity

2015-06-04 | E-GEOD-67387 | biostudies-arrayexpress

The RNA methyltransferase METTL8 installs m3C32 in mitochondrial tRNAsThr/Ser(UCN) to optimise tRNA structure and mitochondrial translation

Project description:Modified nucleotides in tRNAs are important determinants of folding, structure and function. Here, we identify METTL8 as a mitochondrial matrix protein and active RNA methyltransferase responsible for installing m3C32 in the human mitochondrial (mt-)tRNAThr and mt-tRNASer(UCN). METTL8 crosslinks to the anticodon stem loop (ASL) of many mt-tRNAs in cells, raising the question of how methylation target specificity is achieved. Dissection of mt-tRNA recognition elements revealed U34G35 and t6A37/(ms2)i6A37, present concomitantly only in the ASLs of the two substrate mt-tRNAs, as key determinations for METTL8-mediated methylation of C32. Several lines of evidence demonstrate the influence of U34, G35, and the m3C32 and t6A37/(ms2)i6A37 modifications in mt-tRNAThr/Ser(UCN) on the structure of these mt-tRNAs. Although mt-tRNAThr/Ser(UCN) lacking METTL8-mediated m3C32 are efficiently aminoacylated and associate with mitochondrial ribosomes, mitochondrial translation is mildly impaired by lack of METTL8. Together these results define the cellular targets of METTL8 and shed new light on the role of m3C32 within mt-tRNAs.

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The RNA methyltransferase METTL8 installs m3C32 in mitochondrial tRNAsThr/Ser(UCN) to optimise tRNA structure and mitochondrial translation

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Expression data from polysomal, nonpolysomal, and total RNAs in the S. cerevisiae tRNA trafficking mutants, msn5 and mtr10

Project description:tRNAs are transcribed and partially processed in the nucleus before they are exported to the cytoplasm where they have an essential role in protein synthesis. Surprisingly, mature cytoplasmic tRNAs shuttle between nucleus and cytoplasm and its distribution is nutrient-dependent. At least three members of M-NM-2-importin family, Los1, Mtr10, and Msn5, function in tRNA nuclear-cytoplasmic intracellular movement. To test the hypothesis that the tRNA retrograde pathway regulates translation of particular transcripts We compared individual translation activity index (P/NP), obtained from the ratio of polysome-associated (P) to not associated (non-polysomal, NP) mRNAs, in the msn5M-NM-^T, mtr10M-NM-^T, and wild-type cells under fed or acute amino acid depletion conditions Polysome associated (P), not associated (non-polysomal, NP), and total (T) RNAs were isolated from yeast cells, including wild-type (BY4742), msn5 deletion, mtr10 deletion, grown in fed and 30-min amino acid starvation conditions

2013-09-01 | E-GEOD-47713 | biostudies-arrayexpress

NanoCAGE in ERα knockdown BM67 cells

Project description:NanoCAGE in ERα knockdown BM67 cells

| PRJNA494966 | ENA

TSAA

Project description:Translational regulation can be studied on a global scale by integrating polysome fractionation of mRNAs with microarray hybridization. This approach is based on the fact that translationally quiescent mRNAs are sequestered within messenger ribonucleoprotein (mRNP) particles or associated with single ribosomes (monosomes), whereas actively translated mRNAs are associated with multiple ribosomes (polysomes). The mRNAs associated within these fractions are then used to interrogate microarrays, providing insight into how the translational state of individual mRNAs is modified by environmental cues. In this study, we coupled polysome fractionation with microarray detection in order to identify changes in the translation state of the A. fumigatus transcriptome under conditions that perturb ER homeostasis such as chemical stress (DTT, tunicamycin) or thermal stress (shift from 25 degrees celsius to 37 degrees celsius).

2014-10-24 | E-MTAB-2027 | biostudies-arrayexpress

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