Article

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

Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Genome Research (Impact Factor: 13.85). 09/2010; 20(9):1207-18. DOI: 10.1101/gr.106849.110
Source: PubMed

ABSTRACT 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

Full-text

Available from: Haiyang Hu, Jul 02, 2015
0 Followers
 · 
186 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Aging is thought to be associated with increased molecular damage, but representative markers vary across conditions and organisms, making it difficult to assess properties of cumulative damage throughout lifespan. We used nontargeted metabolite profiling to follow age-associated trajectories of >15,000 metabolites in Drosophila subjected to control and lifespan-extending diets. We find that aging is associated with increased metabolite diversity and low-abundance molecules, suggesting they include cumulative damage. Remarkably, the number of detected compounds leveled-off in late-life, and this pattern associated with survivorship. Fourteen percent of metabolites showed age-associated changes, which decelerated in late-life and long-lived flies. In contrast, known metabolites changed in abundance similarly to nontargeted metabolites and transcripts, but did not increase in diversity. Targeted profiling also revealed slower metabolism and accumulation of lifespan-limiting molecules. Thus, aging is characterized by gradual metabolome remodeling, and condition- and advanced age-associated deceleration of this remodeling is linked to mortality and molecular damage.DOI: http://dx.doi.org/10.7554/eLife.02077.001.
    eLife Sciences 04/2014; 3:e02077. DOI:10.7554/eLife.02077 · 8.52 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Genome-wide association studies (GWAS) identified the MEIS1 locus for Restless Legs Syndrome (RLS), but causal single nucleotide polymorphisms (SNPs) and their functional relevance remain unknown. This locus contains a large number of highly conserved noncoding regions (HCNRs) potentially functioning as cis-regulatory modules. We analyzed these HCNRs for allele-dependent enhancer activity in zebrafish and mice and found that the risk allele of the lead SNP rs12469063 reduces enhancer activity in the Meis1 expression domain of the murine embryonic ganglionic eminences (GE). CREB1 binds this enhancer and rs12469063 affects its binding in vitro. In addition, MEIS1 target genes suggest a role in the specification of neuronal progenitors in the GE, and heterozygous Meis1-deficient mice exhibit hyperactivity, resembling the RLS phenotype. Thus, in vivo and in vitro analysis of a common SNP with small effect size showed allele-dependent function in the prospective basal ganglia representing the first neurodevelopmental region implicated in RLS.
    Genome Research 03/2014; DOI:10.1101/gr.166751.113 · 13.85 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Microglia develop an inflammatory phenotype during normal aging. The mechanism by which this occurs is not well understood, but might be related to impairments in several key immunoregulatory systems. Here we show that micro-RNA (miR)-29a and miR-29b, 2 immunoregulatory micro-RNAs, were increased in the brain of aged BALB/c mice compared with adults. Insulin-like growth factor-1 (IGF-1) and fractalkine ligand (CX3CL1) are negative modulators of microglial activation and were identified as targets of miR-29a and miR-29b using luciferase assay and primary microglia transfection. Indeed, higher expression of miR-29b in the brain of aged mice was associated with reduced messenger RNA (mRNA) levels of IGF-1 and CX3CL1. Parallel to these results in mice, miR-29a and miR-29b were also markedly increased in cortical brain tissue of older individuals (mean, 77 years) compared with middle-aged adults (mean, 45 years). Moreover, increased expression of miR-29b in human cortical tissue was negatively correlated with IGF-1 and CX3CL1 expression. Collectively, these data indicate that an age-associated increase in miR-29 corresponded with the reduction of 2 important regulators of microglia, IGF-1 and CX3CL1.
    Neurobiology of aging 07/2013; 34(12). DOI:10.1016/j.neurobiolaging.2013.06.007 · 4.85 Impact Factor