Overexpression of eIF-5A2 in mice causes accelerated organismal aging by increasing chromosome instability

Chen, Muhan; Huang, Jian‐Dong; Deng, Hong Kui; Dong, Sui-Sui; Deng, Wen; Tsang, Sze Lan; Huen, Michael S.Y.; Chen, Leilei; Zan, Tao; Zhu, G; Guan, Xin Yuan

doi:10.1186/1471-2407-11-199

Cited by 20 publications

(11 citation statements)

References 28 publications

(34 reference statements)

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“…In in vivo conditions, EIFs were not found between the differentially present transcripts indicating a balance between their usage and later synthesis. In vitro conditions seem to impair this balance and EIF accumulation may reflect accelarated aging caused by increased chromosome instability [82], a phenomenon often seen in oocytes matured in vitro ; or G1 arrest and apoptosis during hypoxic cell culture conditions [83] or serum starvation [84], which often accompany suboptimal embryo culture.…”

Section: Resultsmentioning

confidence: 99%

RNA Profiles of Porcine Embryos during Genome Activation Reveal Complex Metabolic Switch Sensitive to In Vitro Conditions

et al. 2013

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Fertilization is followed by complex changes in cytoplasmic composition and extensive chromatin reprogramming which results in the abundant activation of totipotent embryonic genome at embryonic genome activation (EGA). While chromatin reprogramming has been widely studied in several species, only a handful of reports characterize changing transcriptome profiles and resulting metabolic changes in cleavage stage embryos. The aims of the current study were to investigate RNA profiles of in vivo developed (ivv) and in vitro produced (ivt) porcine embryos before (2-cell stage) and after (late 4-cell stage) EGA and determine major metabolic changes that regulate totipotency. The period before EGA was dominated by transcripts responsible for cell cycle regulation, mitosis, RNA translation and processing (including ribosomal machinery), protein catabolism, and chromatin remodelling. Following EGA an increase in the abundance of transcripts involved in transcription, translation, DNA metabolism, histone and chromatin modification, as well as protein catabolism was detected. The further analysis of members of overlapping GO terms revealed that despite that comparable cellular processes are taking place before and after EGA (RNA splicing, protein catabolism), different metabolic pathways are involved. This strongly suggests that a complex metabolic switch accompanies EGA. In vitro conditions significantly altered RNA profiles before EGA, and the character of these changes indicates that they originate from oocyte and are imposed either before oocyte aspiration or during in vitro maturation. IVT embryos have altered content of apoptotic factors, cell cycle regulation factors and spindle components, and transcription factors, which all may contribute to reduced developmental competence of embryos produced in vitro. Overall, our data are in good accordance with previously published, genome-wide profiling data in other species. Moreover, comparison with mouse and human embryos showed striking overlap in functional annotation of transcripts during the EGA, suggesting conserved basic mechanisms regulating establishment of totipotency in mammalian development.

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Section: Resultsmentioning

confidence: 99%

RNA Profiles of Porcine Embryos during Genome Activation Reveal Complex Metabolic Switch Sensitive to In Vitro Conditions

et al. 2013

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“…The p.P19S (rs384285149) variant in EIF5A2 is predicted to be highly damaging to protein function ( SIFT -score: 0.00; Polyphen -score: 0.952; Additional file 2 ). Differential expression of EIF5A2 is associated with severe growth retardation and a reduced lifespan in mice [ 17 ]. p.P19S is therefore a plausible candidate mutation for an increased juvenile mortality.…”

Section: Resultsmentioning

confidence: 99%

Homozygous haplotype deficiency reveals deleterious mutations compromising reproductive and rearing success in cattle

Pausch¹,

Schwarzenbacher²,

Burgstaller

et al. 2015

BMC Genomics

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BackgroundCattle breeding populations are susceptible to the propagation of recessive diseases. Individual sires generate tens of thousands of progeny via artificial insemination. The frequency of deleterious alleles carried by such sires may increase considerably within few generations. Deleterious alleles manifest themselves often by missing homozygosity resulting from embryonic/fetal, perinatal or juvenile lethality of homozygotes.ResultsA scan for homozygous haplotype deficiency in 25,544 Fleckvieh cattle uncovered four haplotypes affecting reproductive and rearing success. Exploiting whole-genome resequencing data from 263 animals facilitated to pinpoint putatively causal mutations in two of these haplotypes. A mutation causing an evolutionarily unlikely substitution in SUGT1 was perfectly associated with a haplotype compromising insemination success. The mutation was not found in homozygous state in 10,363 animals (P = 1.79 × 10−5) and is thus likely to cause lethality of homozygous embryos. A frameshift mutation in SLC2A2 encoding glucose transporter 2 (GLUT2) compromises calf survival. The mutation leads to premature termination of translation and activates cryptic splice sites resulting in multiple exon variants also with premature translation termination. The affected calves exhibit stunted growth, resembling the phenotypic appearance of Fanconi-Bickel syndrome in humans (OMIM 227810), which is also caused by mutations in SLC2A2.ConclusionsExploiting comprehensive genotype and sequence data enabled us to reveal two deleterious alleles in SLC2A2 and SUGT1 that compromise pre- and postnatal survival in homozygous state. Our results provide the basis for genome-assisted approaches to avoiding inadvertent carrier matings and to improving reproductive and rearing success in Fleckvieh cattle.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1483-7) contains supplementary material, which is available to authorized users.

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“…Apart from nuclear architecture and organization, increased DNA lesions and genome instability also contribute to aging. Disruption of DNA repair mechanisms or the spindle assembly checkpoint (SAC), which ensures chromosome transmission fidelity, results in accelerated aging (Chen et al, 2011;Gregg et al, 2012;Krishnan et al, 2011;Murga et al, 2009). Accordingly, enhancing SAC activity through overexpression of BubR1, a key component of the checkpoint, prevented aneuploidy in aged mice and extended the lifespan of the animal (Baker et al, 2013;Weaver et al, 2016).…”

Section: Organelle-associated Determinantsmentioning

confidence: 99%

Recent insights into the cellular and molecular determinants of aging

Ruan

Zhang

2018

Journal of Cell Science

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Aging is the gradual decline of physiological functions and organismal fitness, which leads to age-dependent fitness loss, diseases and eventually mortality. Understanding the cause of aging constitutes one of most intriguing areas of research in biology. On both the cellular and molecular levels, it has been hypothesized that there are aging determinants to control the onset and progression of aging, including the loss of beneficial components and accumulation of detrimental factors. This Review highlights the recent advance in identifying various factors that affect the aging process, focusing on how these determinants affect the lifespan and fitness of a cell or organism. With more and more aging determinants revealed, further understanding about their functions and interconnections could enable the development of specific intervention to extend healthy lifespan and reduce the risk of age-related diseases.

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Overexpression of eIF-5A2 in mice causes accelerated organismal aging by increasing chromosome instability

Cited by 20 publications

References 28 publications

RNA Profiles of Porcine Embryos during Genome Activation Reveal Complex Metabolic Switch Sensitive to In Vitro Conditions

RNA Profiles of Porcine Embryos during Genome Activation Reveal Complex Metabolic Switch Sensitive to In Vitro Conditions

Homozygous haplotype deficiency reveals deleterious mutations compromising reproductive and rearing success in cattle

Recent insights into the cellular and molecular determinants of aging

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