MicroRNA, mRNA, and protein expression link development and aging in human and macaque

Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Genome Research (Impact Factor: 14.63). 09/2010; 20(9):1207-18. DOI: 10.1101/gr.106849.110
Source: PubMed


Changes in gene expression levels determine differentiation of tissues involved in development and are associated with functional decline in aging. Although development is tightly regulated, the transition between development and aging, as well as regulation of post-developmental changes, are not well understood. Here, we measured messenger RNA (mRNA), microRNA (miRNA), and protein expression in the prefrontal cortex of humans and rhesus macaques over the species' life spans. We find that few gene expression changes are unique to aging. Instead, the vast majority of miRNA and gene expression changes that occur in aging represent reversals or extensions of developmental patterns. Surprisingly, many gene expression changes previously attributed to aging, such as down-regulation of neural genes, initiate in early childhood. Our results indicate that miRNA and transcription factors regulate not only developmental but also post-developmental expression changes, with a number of regulatory processes continuing throughout the entire life span. Differential evolutionary conservation of the corresponding genomic regions implies that these regulatory processes, although beneficial in development, might be detrimental in aging. These results suggest a direct link between developmental regulation and expression changes taking place in aging.

Download full-text


Available from: Haiyang Hu,
66 Reads
  • Source
    • "In the only study of this kind of which we are aware, Somel et al. (2010)) were able to map parallel developmental and aging changes in microRNAs (miRs) and messenger RNAs (mRNAs) in gross samples of the surface-accessible superior frontal gyrus from frozen postmortem brains of healthy Rhesus macaque, and in the same region which had been dissected from frozen healthy human brains obtained from an NICHD/NIH-sponsored repository of frozen human brains. Relevantly, the major changes in gene expression in NHP and human superior frontal gyrus coordinately change with age when differences in lifespan are taken into account (Somel et al., 2010). However, it is not known to what extent other parts of the brain parallel these findings, including components of the fronto-limbic circuit, Furthermore, inasmuch as most repositories of diseased and control human brains are often available only in an intact, frozen state, it is a challenge to access and isolate centrally located brain regions. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Fronto-limbic circuits in the primate brain are responsible for executive function, learning and memory, and emotions, including fear. Consequently, changes in gene expression in cortical and subcortical brain regions housing these circuits are associated with many important psychiatric and neurological disorders. While high quality gene expression profiles can be identified in brains from model organisms, primate brains have unique features such as Brodmann Area 25, which is absent in rodents, yet profoundly important in primates, including humans. The potential insights to be gained from studying the human brain are complicated by the fact that the post-mortem interval (PMI) is variable, and most repositories keep solid tissue in the deep frozen state. Consequently, sampling the important medial and internal regions of these brains is difficult. Here we describe a novel method for obtaining discrete regions from the fronto-limbic circuits of a 4 year old and a 5 year old, male, intact, frozen non-human primate (NHP) brain, for which the PMI is exactly known. The method also preserves high quality RNA, from which we use transcriptional profiling and a new algorithm to identify region-exclusive RNA signatures for Area 25 (NFκB and dopamine receptor signaling), the anterior cingulate cortex (LXR/RXR signaling), the amygdala (semaphorin signaling), and the hippocampus (Ca++ and retinoic acid signaling). The RNA signatures not only reflect function of the different regions, but also include highly expressed RNAs for which function is either poorly understood, or which generate proteins presently lacking annotated functions. We suggest that this new approach will provide a useful strategy for identifying changes in fronto-limbic system biology underlying normal development, aging and disease in the human brain.
    Brain Research 12/2014; 1600. DOI:10.1016/j.brainres.2014.12.031 · 2.84 Impact Factor
  • Source
    • "Analysis of the expression level of miR-34a in the PM control samples revealed a pronounced postnatal increase in expression that plateaus after the teenage years. Age-dependent elevation of miR-34a expression in brain and cardiac tissue has previously been reported (Somel et al. 2010; Li et al. 2011; Boon et al. 2013). Since our pediatric subjects are within the timeframe of rapid increase in miR-34a expression, it is imperative that we consider subject age when investigating microRNA expression events in this population. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tuberous sclerosis complex (TSC) is a multisystem genetic disorder caused by mutations in the TSC1 and TSC2 genes. Over 80% of TSC patients are affected by epilepsy, but the molecular events contributing to seizures in TSC are not well understood. Recent reports have demonstrated that the brain is enriched with microRNA activity, and they are critical in neural development and function. However, little is known about the role of microRNAs in TSC. Here, we report the characterization of aberrant microRNA activity in cortical tubers resected from 5 TSC patients surgically treated for medically intractable epilepsy. By comparing epileptogenic tubers with adjacent nontuber tissue, we identified a set of 4 coordinately overexpressed microRNAs (miRs 23a, 34a, 34b*, 532-5p). We used quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteomic profiling to investigate the combined effect of the 4 microRNAs on target proteins. The proportion of repressed proteins among the predicted targets was significantly greater than in the overall proteome and was highly enriched for proteins involved in synaptic signal transmission. Among the combinatorial targets were TSC1, coding for the protein hamartin, and several epilepsy risk genes. We found decreased levels of hamartin in epileptogenic tubers and confirmed targeting of the TSC1 3' UTR by miRs-23a and 34a. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail:
    Cerebral Cortex 12/2014; DOI:10.1093/cercor/bhu276 · 8.67 Impact Factor
  • Source
    • "Metabolite trajectories were gradual and continuous starting from early adulthood, with very few signals showing mid-life reversals. These results are generally consistent with the observations from the studies on transcript and protein profiles across diverse aging populations (Zou et al., 2000; Pletcher et al., 2002; Somel et al., 2010). Indeed, our analysis of age-associated gene expression involving both control and dietary restricted long-lived individuals indicates that metabolites and transcripts exhibit nearly identical frequencies of dietdependent to diet-independent effects. "
    [Show abstract] [Hide abstract]
    ABSTRACT: eLife digest Signs of aging have been observed in many different species, but the underlying mechanisms are still poorly understood. It is thought that aging is influenced by metabolism. For example, scientists have found that metabolism can lead to the accumulation of byproducts, which may cause damage to cells. Moreover, as organisms get older, the diversity of these byproducts can increase. However, it has proven difficult to measure this cumulative damage. Avanesov et al. have now tried a different approach and examined the relationship between cellular metabolism, lifespan, and cumulative damage. Male fruit flies were raised on one of two diets—a standard diet, or a restrictive diet that extends their lifespan—and a technique called metabolite profiling was then used to monitor more than 15,000 metabolites in both sets of flies. Avanesov et al. found that the number of metabolites increased over time, suggesting that damage or mistakes in molecular synthesis increased with age. But the number of metabolites reached a plateau in the oldest flies, even in those whose lifespans were artificially extended. This could be due to cells becoming less active as they get very old. Avanesov et al. also found that the profile of the metabolites changed in a way that was similar to the way that patterns of gene transcription changed. This suggests that there may be a link between transcription—which is the first step in the process that produces proteins in cells—and metabolism and aging. DOI:
    eLife Sciences 04/2014; 3(3):e02077. DOI:10.7554/eLife.02077 · 9.32 Impact Factor
Show more