Abstract
BackgroundMammalian aging is a highly complex process, a full mechanistic understanding of which is still lacking. One way to help understand the molecular changes underlying aging is through a comprehensive analysis of the transcriptome, the primary determinant of age-related phenotypic diversity. Previous studies have relied on microarray analysis to examine gene expression profiles in different tissues of aging organisms. However, studies have shown microarray-based transcriptional profiling is less accurate and not fully capable of capturing certain intricacies of the global transcriptome.MethodsHere, using directional whole transcriptome RNA-sequencing of aged mouse liver we have identified a comprehensive high-resolution profile of differentially expressed liver transcripts comprised of canonical protein-coding transcripts, transcript isoforms, and non-coding RNA transcripts, including pseudogenes, long non-coding RNAs and small RNA species.ResultsResults show extensive age-related changes in every component of the mouse liver transcriptome and a pronounced increase in inter-individual variation. Functional annotation of the protein-coding mRNAs and isoforms indicated broad alterations in immune response, cell activation, metabolic processes, and RNA modification. Interestingly, multiple lncRNAs (Meg3, Rian, Mirg) from the Dlk-Dio3 microRNA locus were found up-regulated in aging liver, classifying this locus as a putative regulatory hotspot locus in aging liver. Moreover, integration of the altered non-coding RNAs and protein-coding transcripts into interaction networks of age-related change revealed inflammation, cellular proliferation, and metabolism as the dominant aging phenotypes in mouse liver.ConclusionsOur analyses provide the first comprehensive dissection of the transcriptional landscape in aging mouse liver.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-2061-8) contains supplementary material, which is available to authorized users.
Highlights
Mammalian aging is a highly complex process, a full mechanistic understanding of which is still lacking
Sequencing metrics and transcriptome genomic coverage To directly analyze the global transcriptome of aging mouse liver, we isolated total RNA from three young adult (4 months) and three old (28 months) male mouse livers and performed directional whole transcriptome sequencing [16]
We found that the percentage for each category of transcript of total normalized counts is generally more variable for old livers as compared to young (Fig. 2e). These findings indicate that the liver transcriptome from aged mice is consistently more variable than that from young mice and that this increased inter-individual variation is attributable, in part, to the stochastic variation observed at the level of specific transcript types
Summary
Mammalian aging is a highly complex process, a full mechanistic understanding of which is still lacking. To increase our understanding of the different interacting processes that underlie agerelated organ and tissue degeneration, a systematic study of alterations in gene expression is a logical starting point. White et al BMC Genomics (2015) 16:899 such as non-coding (nc)RNAs. White et al BMC Genomics (2015) 16:899 such as non-coding (nc)RNAs This is especially important for non-coding RNAs since the role of this category of transcripts is generally understood to involve fine-tuning gene regulatory patterns, such as cellular metabolism [10]. Increased deregulation at this level could potentially explain many of the aging phenotypes observed, which involve subtle rather than dramatic changes. Recent advances in RNA sequencing offer a suitable alternative to studying variation in gene expression that addresses all of these issues
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