Poor transcript‐protein correlation in the brain: negatively correlating gene products reveal neuronal polarity as a potential cause

Abstract

Transcription, translation, and turnover of transcripts and proteins are essential for cellular function. The contribution of those factors to protein levels is under debate, as transcript levels and cognate protein levels do not necessarily correlate due to regulation of translation and protein turnover. Here we propose neuronal polarity as a third factor that is particularly evident in the CNS, leading to considerable distances between somata and axon terminals. Consequently, transcript levels may negatively correlate with cognate protein levels in CNS regions, i.e., transcript and protein levels behave reciprocally. To test this hypothesis, we performed an integrative interomics study and analyzed three interconnected rat auditory brainstem regions (cochlear nuclear complex, CN; superior olivary complex, SOC; inferior colliculus, IC) and the rest of the brain as a reference. We obtained transcript and protein sets in these regions of interest (ROIs) by DNA microarrays and labelfree mass spectrometry, and performed principal component and correlation analyses. We found 508 transcript|protein pairs and detected poor to moderate transcript|protein correlation in all ROIs, as evidenced by coefficients of determination from 0.34 to 0.54. We identified 57-80 negatively correlating gene products in the ROIs and intensively analyzed four of them for which the correlation was poorest. Three cognate proteins (Slc6a11, Syngr1, Tppp) were synaptic and hence candidates for a negative correlation because of protein transport into axon terminals. Thus, we systematically analyzed the negatively correlating gene products. Gene ontology analyses revealed overrepresented transport/synapse-related proteins, supporting our hypothesis. We present 30 synapse/transport-related proteins with poor transcript|protein correlation. In conclusion, our analyses support that protein transport in polar cells is a third factor that influences the protein level and, thereby, the transcript|protein correlation.Abbreviations used: CN, cochlear nuclear complex; CNS, central nervous system; cRNA, complementary RNA; CV%, relative coefficient of variation; DNA, deoxyribonucleic acid; GO, gene ontology; IC, inferior colliculus; MA (plot)l, og ratio versus mean average (plot); mRNA, messenger RNA; PC, principal component; QI -QIV, quadrant Iquadrant IV; RNA, ribonucleic acid; RoB, rest of brain; ROI, region of interest; RRID, research resource identifiers; SILAC, stable isotope labeling by amino acids in cell culture; SOC, superior olivary complex.

Unique IL-13Rα2/STAT3 mediated IL-13 regulation detected in lung conventional dendritic cells, 24 h post viral vector vaccination

“…Moreover, this was further substantiated by the presence of elevated stable IL-13Rα2 protein and minimal mRNA expression at 24 h post rFPV vaccination, elucidating a distinct inverse protein-mRNA regulation, unlike IL-13 mediated inflammatory conditions 2,[35][36][37][38] . Non-linear protein-mRNA regulation of other proteins 39,40 , cytokines, including IL-13 41 specifically, elevated protein and rapid mRNA degradation associated with protein stability have been previously documented [42][43][44] . Moreover, presence of minimal Il13ra2 transcript levels in most mouse tissue types at steady-state 1,35,37,38,45 (NCBI Gene ID: 16165) and in human cancers post-transcriptional regulation of IL-13Rα2 by alternative epigenetic pathways have also been reported 46 .…”

Peroxiredoxin 4 as potential fertility marker in boars

“…In contrast to PRDX 4 mRNA levels, total Prdx 4 protein levels negatively correlated with the litter size (r = -0.539). This inverse pattern between mRNA and protein levels of PRDX 4 might be explained by several factors, including regulation of translation and protein stability (46)(47)(48). Although difficult to explain, understanding the basis of this inverse correlation will be critical to explaining the relevance of PRDX 4 transcript and protein markers.…”

Multiplexed and Inducible Gene Modulation in Human Pluripotent Stem Cells by CRISPR Interference and Activation

“…This discrepancy may arise in cases where only a small percentage of the expressed transcripts are needed to maintain cellular protein levels or cases when the protein is more stable than the transcript (Schwanhäusser et al, 2011). Such transcription-translation discrepancies are mediated by endogenous regulatory programs that vary from cell-type to cell-type (Moritz et al, 2019) and remain an important aspect to consider in both single gene studies and whole genome screens with CRISPRi and CRISPRa strategies.…”