Abstract
BackgroundIn studies of development and aging, the expression of many genes has been shown to undergo drastic changes at mRNA and protein levels. The connection between mRNA and protein expression level changes, as well as the role of posttranscriptional regulation in controlling expression level changes in postnatal development and aging, remains largely unexplored.ResultsHere, we survey mRNA and protein expression changes in the prefrontal cortex of humans and rhesus macaques over developmental and aging intervals of both species’ lifespans. We find substantial decoupling of mRNA and protein expression levels in aging, but not in development. Genes showing increased mRNA/protein disparity in primate brain aging form expression patterns conserved between humans and macaques and are enriched in specific functions involving mammalian target of rapamycin (mTOR) signaling, mitochondrial function and neurodegeneration. Mechanistically, aging-dependent mRNA/protein expression decoupling could be linked to a specific set of RNA binding proteins and, to a lesser extent, to specific microRNAs.ConclusionsIncreased decoupling of mRNA and protein expression profiles observed in human and macaque brain aging results in specific co-expression profiles composed of genes with shared functions and shared regulatory signals linked to specific posttranscriptional regulators. Genes targeted and predicted to be targeted by the aging-dependent posttranscriptional regulation are associated with biological processes known to play important roles in aging and lifespan extension. These results indicate the potential importance of posttranscriptional regulation in modulating aging-dependent changes in humans and other species.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0608-2) contains supplementary material, which is available to authorized users.
Highlights
In studies of development and aging, the expression of many genes has been shown to undergo drastic changes at mRNA and protein levels
Most knowledge of RNA binding protein (RBP) binding sites has been obtained through large-scale crosslinking and immunoprecipitation (CLIP) experiments, including high-throughput sequencing of RNA isolated by CLIP (HITS-CLIP) [9], Wei et al Genome Biology (2015) 16:41 photoactivatable-ribonucleoside-enhanced CLIP (PARCLIP) [10], and individual nucleotide resolution CLIP [11]
Our results further indicate that all four patterns of aging-dependent mRNA/protein expression decoupling can be associated with a small number of key regulatory RBPs, such as SFRS1, TIAL1 and AGO2
Summary
In studies of development and aging, the expression of many genes has been shown to undergo drastic changes at mRNA and protein levels. The connection between mRNA and protein expression level changes, as well as the role of posttranscriptional regulation in controlling expression level changes in postnatal development and aging, remains largely unexplored. Posttranscriptional regulation has been shown to contribute to the fine-tuning of gene expression in such cellular processes as apoptosis, immune response, inflammation, neuronal differentiation, synaptic plasticity, the cell cycle, and oncogenesis [1,2,3]. Despite the relatively small number of studies focusing on RBPs, these proteins have been shown to play important roles in controlling splicing, polyadenylation, stability, editing, localization, and translational efficiency of RNA transcripts in human tissues and cell lines [5]
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