Blood miRNomes and transcriptomes reveal novel longevity mechanisms in the long-lived bat, Myotis myotis

Abstract

BackgroundChiroptera, the bats, are the only order of mammals capable of true self-powered flight. Bats exhibit a number of other exceptional traits such as echolocation, viral tolerance and, perhaps most puzzlingly, extreme longevity given their body size. Little is known about the molecular mechanisms driving their extended longevity particularly at the levels of gene expression and post-transcriptional regulation. To elucidate the molecular mechanisms that may underlie their unusual longevity, we have deep sequenced 246.5 million small RNA reads from whole blood of the long-lived greater mouse-eared bats, Myotis myotis, and conducted a series of genome-wide comparative analyses between bat and non-bat mammals (human, pig and cow) in both blood miRNomes and transcriptomes, for the first time.ResultsWe identified 539 miRNA gene candidates from bats, of which 468 unique mature miRNA were obtained. More than half of these miRNA (65.1 %) were regarded as bat-specific, regulating genes involved in the immune, ageing and tumorigenesis pathways. We have also developed a stringent pipeline for genome-wide miRNome comparisons across species, and identified 37 orthologous miRNA groups shared with bat, human, pig and cow, 6 of which were differentially expressed. For bats, 3 out of 4 up-regulated miRNA (miR-101-3p, miR-16-5p, miR-143-3p) likely function as tumor suppressors against various kinds of cancers, while one down-regulated miRNA (miR-221-5p) acts as a tumorigenesis promoter in human breast and pancreatic cancers. Additionally, a genome-wide comparison of mRNA transcriptomes across species also revealed specific gene expression patterns in bats. 127 up-regulated genes were enriched mainly in mitotic cell cycle and DNA repair mechanisms, while 364 down-regulated genes were involved primarily in mitochondrial activity.ConclusionsOur comprehensive and integrative analyses revealed bat-specific and differentially expressed miRNA and mRNA that function in key longevity pathways, producing a distinct bat gene expression pattern. For the first time, we show that bats may possess unique regulatory mechanisms for resisting tumorigenesis, repairing cellular damage and preventing oxidative stresses, all of which likely contribute to the extraordinary lifespan of Myotis myotis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3227-8) contains supplementary material, which is available to authorized users.

A comprehensive annotation and differential expression analysis of short and long non-coding RNAs in 16 bat genomes

“…Bats have developed a variety of unique biological features that are the rarest among all mammalian, including laryngeal echolocation 4,6 , vocal learning 7 , and the ability to fly 3 . They occupy a broad range of different ecological niches 2 , have an exceptional longevity [8][9][10] and a natural and unique resilience against various pathogenic viruses 1,11 .…”

Bat Biology, Genomes, and the Bat1K Project: To Generate Chromosome-Level Genomes for All Living Bat Species

“…However, the maintenance of function alone is not enough, as cells and tissues need constant repair over the course of a multiyear life span. Studies focused on bats have identified suites of cellular repair mechanisms that potentially evolved to support the unusual longevity of bats (11,40,44,45). These genes and variants can be readily compared with human genes to discover specific features that would enable a healthy old age (11,44,45).…”

“…This in turn has led them to evolve the relatively unusual vertebrate combination of long life spans with small bodies (17,40,43). As long-lived mammals, in some cases living >41 years, bats offer clues regarding the mechanisms for maintaining high function across internal systems over a long life span, longer than any similar-sized mouse can live (17,44,45). Natural selection over millions of generations for continued health and reproduction throughout a long lifetime has equipped bats with excellent cellular and system-wide mechanisms of maintenance (45).…”

“…As long-lived mammals, in some cases living >41 years, bats offer clues regarding the mechanisms for maintaining high function across internal systems over a long life span, longer than any similar-sized mouse can live (17,44,45). Natural selection over millions of generations for continued health and reproduction throughout a long lifetime has equipped bats with excellent cellular and system-wide mechanisms of maintenance (45). This is particularly impressive considering that the high metabolic rates characteristic of bats are expected to produce reactive oxygen species, typically causing chronic inflammation and hastening senescence (46).…”

“…Techniques to understand regulatory networks, including small RNAs, transcription factor cascades (e.g., ChIP-Seq, enhancer mapping), epigenetic marks, and chromatin structure (e.g., histone mapping, chromatin conformation capture, topological domain mapping), rely on a comprehensive understanding of the identity and position of both coding and noncoding DNA sequences (154)(155)(156). The perturbation of regulatory networks represents a particularly powerful way to invoke evolutionary change without the need to evolve novel genes (45). Such perturbations have been suggested as influential in bat diversification (157).…”