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Comparative analysis of long noncoding RNAs in long-lived mammals provides insights into natural cancer-resistance.

ABSTRACT: Mouse and rats are staple model organisms that have been traditionally used for oncological studies; however, their short lifespan and highly prone to cancers limit their utilizationsin understanding the mechanisms of cancer resistance. In recent years, several studies of the non-standard long-lived mammalian species like naked mole rat (NMR) have provided new insights of mechanisms in natural anti-cancer. How long-lived species genetically maintain longevity and cancer-resistance remains largely elusive. To better understand the underlying anti-cancer mechanisms in long-lived mammals, we genome widely identified long noncoding RNA (lncRNA) transcripts of two longevous mammals, bowhead whale (BW, Balaena mysticetus) and Brandt's bat (BB, Myotis brandtii) and featured their sequence traits, expression patterns, and their correlations with cancer-resistance. Similar with naked mole rat (NMR, Heterocephalus glaber), the most long-lived rodent, BW and BB lncRNAs show low sequence conservation and dynamic expressions among tissues and physiological stages. By utilizing k-mers clustering, 75-136 of BW, BB and NMR lncRNAs were found in close relation (Pearson's r ≥0.9, p < 0.01) with human ageing diseases related lncRNAs (HAR-Lncs). In addition, we observed thousands of BB and BW lncRNAs strongly co-expressed (r > 0.8 or r <-0.8, p < 0.01) with potential tumour suppressors, indicating that lncRNAs are potentially involved in anti-cancer regulation in long-lived mammals. Our study provides the basis for lncRNA researches in perspectives of evolution and anti-cancer studies. Abbreviations: BW: bowhead whale; BB: Brandt's bat; NMR: naked mole rat; LLM: long-lived mammal; HTS: human tumour-suppressors; PTS: potential tumour suppressor; ARD: ageing related diseases; HAR-Lncs: lncRNAs that related with human ageing diseases; Kmer-lncs: lncRNAs in long-lived mammal species that corelated (Pearson'sr ≥0.9, p < 0.01) with the 10 HAR-Lncs by k-mers clustering; All-lncs: all the lncRNAs in long-lived mammal species; SDE-lncs: significant differentially expressed lncRNAs.

SUBMITTER: Jiang JJ

PROVIDER: S-EPMC7567513 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundSenescence has been widely detected among mammals, but its importance to fitness in wild populations remains controversial. According to evolutionary theories, senescence occurs at an age when selection is relatively weak, which in mammals can be predicted by adult survival rates. However, a recent analysis of senescence rates found more age-dependent mortalities in natural populations of longer lived mammal species. This has important implications to ageing research and for understanding the ecological relevance of senescence, yet so far these have not been widely appreciated. We re-address this question by comparing the mean and maximum life span of 125 mammal species. Specifically, we test the hypothesis that senescence occurs at a younger age relative to the mean natural life span in longer lived species.Methodology/principal findingsWe show, using phylogenetically-informed generalised least squares models, a significant log-log relationship between mean life span, as calculated from estimates of adult survival for natural populations, and maximum recorded life span among mammals (R2=0.57, p<0.0001). This provides further support for a key prediction of evolutionary theories of ageing. The slope of this relationship (0.353+/-0.052 s.e.m.), however, indicated that mammals with higher survival rates have a mean life span representing a greater fraction of their potential maximum life span: the ratio of maximum to mean life span decreased significantly from >10 in short-lived to approximately 1.5 in long-lived mammal species.Conclusions/significanceWe interpret the ratio of maximum to mean life span to be an index of the likelihood an individual will experience senescence, which largely determines maximum life span. Our results suggest that senescence occurs at an earlier age relative to the mean life span, and therefore is experienced by more individuals and remains under selection pressure, in long- compared to short-lived mammals. A minimum rate of somatic degradation may ultimately limit the natural life span of mammals. Our results also indicate that senescence and modulating factors like oxidative stress are increasingly important to the fitness of longer lived mammals (and vice versa).

Project description:Tibetan sheep have lived on the Qinghai-Tibetan Plateau for thousands of years and have good adaptability to the hypoxic environment and strong disease resistance. However, the molecular mechanism by which Tibetan sheep adapt to this extreme environment, especially the role of genetic regulation, is still unknown. Emerging evidence suggests that long noncoding RNAs (lncRNAs) participate in the regulation of a diverse range of biological processes. To explore the potential lncRNAs involved in the adaptation to high-altitude hypoxia of Tibetan sheep, we analysed the expression profile of lncRNAs and mRNAs in the liver and lung tissues of sheep using comparative transcriptome analysis between four Tibetan sheep populations (high altitude) and one Hu sheep population (low altitude). The results showed a total of 7848 differentially expressed (DE) lncRNA transcripts, and 22,971 DE mRNA transcripts were detected by pairwise comparison. The expression patterns of selected mRNAs and lncRNAs were validated by qRT-PCR, and the results correlated well with the transcriptome data. Moreover, the functional annotation analysis based on the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases showed that DE mRNAs and the target genes of the lncRNAs were significantly enriched in organ morphogenesis, response to stimulus, haem binding, the immune system, arginine and proline metabolism, and fatty acid biosynthesis. The prediction of mRNA-mRNA and lncRNA-mRNA interaction networks further revealed transcripts potentially involved in adaptation to high-altitude hypoxia, and the hub genes DDX24, PDCD11, EIF4A3, NDUFA11, SART1, PRPF8 and TCONS_00306477, TCONS_00306029, TCONS_00139593, TCONS_00293272, and TCONS_00313398 were selected. Additionally, a set of target genes, PIK3R1, IGF1R, FZD6, IFNB2, ATF3, MB, CYP2B4, PSMD13, and TGFB1, were also identified as candidate genes associated with high-altitude hypoxia adaptation. In conclusion, a collection of novel expressed lncRNAs, a set of target genes and biological pathways known to be relevant for altitude adaptation were identified by comparative transcriptome analysis between Tibetan sheep and Hu sheep. Our results are the first to identify the characterization and expression profile of lncRNAs between Tibetan sheep and Hu sheep and provide insights into the genetic regulation mechanisms by which Tibetan sheep adapt to high-altitude hypoxic environments.

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Comparative analysis of long noncoding RNAs in long-lived mammals provides insights into natural cancer-resistance.

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