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Translating mRNAs strongly correlate to proteins in a multivariate manner and their translation ratios are phenotype specific.

Wang T, Cui Y, Jin J, Guo J, Wang G, Yin X, He QY, Zhang G - Nucleic Acids Res. (2013)

Bottom Line: This correlation highlighted that the mRNA length significantly contributes to the translational modulation, especially to the translational initiation, favoured by its correlation with the mRNA translation ratio (TR) as observed.We found TR is highly phenotype specific, which was substantiated by both pathway analysis and biased TRs of the splice variants of BDP1 gene, which is a key transcription factor of transfer RNAs.These findings revealed, for the first time, the intrinsic and genome-wide translation modulations at translatomic level in human cells at steady-state, which are tightly correlated to the protein abundance and functionally relevant to cellular phenotypes.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China. tongwang@jnu.edu.cn

ABSTRACT
As a well-known phenomenon, total mRNAs poorly correlate to proteins in their abundances as reported. Recent findings calculated with bivariate models suggested even poorer such correlation, whereas focusing on the translating mRNAs (ribosome nascent-chain complex-bound mRNAs, RNC-mRNAs) subset. In this study, we analysed the relative abundances of mRNAs, RNC-mRNAs and proteins on genome-wide scale, comparing human lung cancer A549 and H1299 cells with normal human bronchial epithelial (HBE) cells, respectively. As discovered, a strong correlation between RNC-mRNAs and proteins in their relative abundances could be established through a multivariate linear model by integrating the mRNA length as a key factor. The R(2) reached 0.94 and 0.97 in A549 versus HBE and H1299 versus HBE comparisons, respectively. This correlation highlighted that the mRNA length significantly contributes to the translational modulation, especially to the translational initiation, favoured by its correlation with the mRNA translation ratio (TR) as observed. We found TR is highly phenotype specific, which was substantiated by both pathway analysis and biased TRs of the splice variants of BDP1 gene, which is a key transcription factor of transfer RNAs. These findings revealed, for the first time, the intrinsic and genome-wide translation modulations at translatomic level in human cells at steady-state, which are tightly correlated to the protein abundance and functionally relevant to cellular phenotypes.

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IPA. DEPs and genes with considerable TR fold changes (A549/HBE) were subjected to IPA. (A and B) Heat maps of effects on biological processes, regulated by DEPs (A) and TR-changed genes (B). Top 10 Category Level I bioprocesses are indicated by black blocks. An orange square represents an enhanced Category Level II bioprocess with a positive z-score, provided by IPA, whereas suppressed such bioprocesses, with negative z-scores, are shown in blue squares. Insignificant bioprocesses are indicated by grey squares. (C) The top canonical pathway regulated by TR-changed genes (A549/HBE). Experimentally detected genes are indicated in red shapes, and the colour intensity represents the grade of regulation. Shapes of inversed triangles, circles and squares represent kinases, complexes and cytokines, respectively. Solid and dashed lines with arrows represent direct and indirect promotion, respectively. Full names of the genes (HGNC nomenclature) in red shapes are protease-activated kinase II (p90RSK), cysteine-rich angiogenic inducer 61 (Cyr61), interleulin-8 (IL-8), connective tissue growth factor (CTGF) and heparin-binding EGF-like growth factor (hbEGF).
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gkt178-F5: IPA. DEPs and genes with considerable TR fold changes (A549/HBE) were subjected to IPA. (A and B) Heat maps of effects on biological processes, regulated by DEPs (A) and TR-changed genes (B). Top 10 Category Level I bioprocesses are indicated by black blocks. An orange square represents an enhanced Category Level II bioprocess with a positive z-score, provided by IPA, whereas suppressed such bioprocesses, with negative z-scores, are shown in blue squares. Insignificant bioprocesses are indicated by grey squares. (C) The top canonical pathway regulated by TR-changed genes (A549/HBE). Experimentally detected genes are indicated in red shapes, and the colour intensity represents the grade of regulation. Shapes of inversed triangles, circles and squares represent kinases, complexes and cytokines, respectively. Solid and dashed lines with arrows represent direct and indirect promotion, respectively. Full names of the genes (HGNC nomenclature) in red shapes are protease-activated kinase II (p90RSK), cysteine-rich angiogenic inducer 61 (Cyr61), interleulin-8 (IL-8), connective tissue growth factor (CTGF) and heparin-binding EGF-like growth factor (hbEGF).

Mentions: This increase of computational specificity in TR analysis was also confirmed by effect-on-function assays in IPA (Figure 5). The effects of DEPs on biological processes were largely mixed with contradictory predictions, showing both promotion and inhibition on the same processes (Figure 5A). However, the specificity was improved when analysing TR-changed genes, indicating homogenous regulation on functions (Figure 5B). These TR-predicted and promoted bioprocesses included cell growth and proliferation, cell movement and development, specifically reflecting the features of EMT phenotype of A549 cells (40) (Figure 5B). The top canonical pathway regulated by these TR-changed genes fell into the role of tissue factor in cancer (P = 2.96 × 10−4, Fisher’s Exact test provided by IPA) (Supplementary Figure S5B). The endpoint biological functions regulated by this pathway included cell growth and proliferation, angiogenesis and migration (Figure 5C). With the results shown earlier in the text, TR-based pathway analysis exhibited unique advantages in focusing investigative bioprocesses.Figure 5.


Translating mRNAs strongly correlate to proteins in a multivariate manner and their translation ratios are phenotype specific.

Wang T, Cui Y, Jin J, Guo J, Wang G, Yin X, He QY, Zhang G - Nucleic Acids Res. (2013)

IPA. DEPs and genes with considerable TR fold changes (A549/HBE) were subjected to IPA. (A and B) Heat maps of effects on biological processes, regulated by DEPs (A) and TR-changed genes (B). Top 10 Category Level I bioprocesses are indicated by black blocks. An orange square represents an enhanced Category Level II bioprocess with a positive z-score, provided by IPA, whereas suppressed such bioprocesses, with negative z-scores, are shown in blue squares. Insignificant bioprocesses are indicated by grey squares. (C) The top canonical pathway regulated by TR-changed genes (A549/HBE). Experimentally detected genes are indicated in red shapes, and the colour intensity represents the grade of regulation. Shapes of inversed triangles, circles and squares represent kinases, complexes and cytokines, respectively. Solid and dashed lines with arrows represent direct and indirect promotion, respectively. Full names of the genes (HGNC nomenclature) in red shapes are protease-activated kinase II (p90RSK), cysteine-rich angiogenic inducer 61 (Cyr61), interleulin-8 (IL-8), connective tissue growth factor (CTGF) and heparin-binding EGF-like growth factor (hbEGF).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3643591&req=5

gkt178-F5: IPA. DEPs and genes with considerable TR fold changes (A549/HBE) were subjected to IPA. (A and B) Heat maps of effects on biological processes, regulated by DEPs (A) and TR-changed genes (B). Top 10 Category Level I bioprocesses are indicated by black blocks. An orange square represents an enhanced Category Level II bioprocess with a positive z-score, provided by IPA, whereas suppressed such bioprocesses, with negative z-scores, are shown in blue squares. Insignificant bioprocesses are indicated by grey squares. (C) The top canonical pathway regulated by TR-changed genes (A549/HBE). Experimentally detected genes are indicated in red shapes, and the colour intensity represents the grade of regulation. Shapes of inversed triangles, circles and squares represent kinases, complexes and cytokines, respectively. Solid and dashed lines with arrows represent direct and indirect promotion, respectively. Full names of the genes (HGNC nomenclature) in red shapes are protease-activated kinase II (p90RSK), cysteine-rich angiogenic inducer 61 (Cyr61), interleulin-8 (IL-8), connective tissue growth factor (CTGF) and heparin-binding EGF-like growth factor (hbEGF).
Mentions: This increase of computational specificity in TR analysis was also confirmed by effect-on-function assays in IPA (Figure 5). The effects of DEPs on biological processes were largely mixed with contradictory predictions, showing both promotion and inhibition on the same processes (Figure 5A). However, the specificity was improved when analysing TR-changed genes, indicating homogenous regulation on functions (Figure 5B). These TR-predicted and promoted bioprocesses included cell growth and proliferation, cell movement and development, specifically reflecting the features of EMT phenotype of A549 cells (40) (Figure 5B). The top canonical pathway regulated by these TR-changed genes fell into the role of tissue factor in cancer (P = 2.96 × 10−4, Fisher’s Exact test provided by IPA) (Supplementary Figure S5B). The endpoint biological functions regulated by this pathway included cell growth and proliferation, angiogenesis and migration (Figure 5C). With the results shown earlier in the text, TR-based pathway analysis exhibited unique advantages in focusing investigative bioprocesses.Figure 5.

Bottom Line: This correlation highlighted that the mRNA length significantly contributes to the translational modulation, especially to the translational initiation, favoured by its correlation with the mRNA translation ratio (TR) as observed.We found TR is highly phenotype specific, which was substantiated by both pathway analysis and biased TRs of the splice variants of BDP1 gene, which is a key transcription factor of transfer RNAs.These findings revealed, for the first time, the intrinsic and genome-wide translation modulations at translatomic level in human cells at steady-state, which are tightly correlated to the protein abundance and functionally relevant to cellular phenotypes.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China. tongwang@jnu.edu.cn

ABSTRACT
As a well-known phenomenon, total mRNAs poorly correlate to proteins in their abundances as reported. Recent findings calculated with bivariate models suggested even poorer such correlation, whereas focusing on the translating mRNAs (ribosome nascent-chain complex-bound mRNAs, RNC-mRNAs) subset. In this study, we analysed the relative abundances of mRNAs, RNC-mRNAs and proteins on genome-wide scale, comparing human lung cancer A549 and H1299 cells with normal human bronchial epithelial (HBE) cells, respectively. As discovered, a strong correlation between RNC-mRNAs and proteins in their relative abundances could be established through a multivariate linear model by integrating the mRNA length as a key factor. The R(2) reached 0.94 and 0.97 in A549 versus HBE and H1299 versus HBE comparisons, respectively. This correlation highlighted that the mRNA length significantly contributes to the translational modulation, especially to the translational initiation, favoured by its correlation with the mRNA translation ratio (TR) as observed. We found TR is highly phenotype specific, which was substantiated by both pathway analysis and biased TRs of the splice variants of BDP1 gene, which is a key transcription factor of transfer RNAs. These findings revealed, for the first time, the intrinsic and genome-wide translation modulations at translatomic level in human cells at steady-state, which are tightly correlated to the protein abundance and functionally relevant to cellular phenotypes.

Show MeSH
Related in: MedlinePlus