Sexual activity and/or reproduction are associated with a doubling of life expectancy in the long-lived rodent genus Fukomys. To investigate the molecular mechanisms underlying this phenomenon, we analyzed 636 RNA-seq samples across 15 tissues. This analysis suggests that changes in the regulation of the hypothalamic-pituitary-adrenal stress axis play a key role regarding the extended life expectancy of reproductive vs. non-reproductive mole-rats. This is substantiated by a corpus of independent evidence. In accordance with previous studies, the up-regulation of the proteasome and so-called "anti-aging molecules", e.g. DHEA, is linked with enhanced lifespan. On the other hand, several of our results are not consistent with knowledge about aging of short-lived model organisms. For example, we found the up-regulation of the IGF1/GH axis and several other anabolic processes to be compatible with a considerable lifespan prolongation. These contradictions question the extent to which findings from short-lived species can be transferred to longer-lived ones.
Read datasets generated during the current study are available in the European Nucleotide Archive, study ID: PRJEB29798.
Transcriptome signatures of fast vs. slow aging in Fukomys mole-rat breeders vs. non-breedersEuropean Nucleotide Archive, PRJEB29798.
- Matthias Platzer
- Philip Dammann
- Magdalena Staniszewska
- Magdalena Staniszewska
- Arne Sahm
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: Animal housing and tissue collection were compliant with national and state legislation (breeding allowances 32-2-1180-71/328 and 32-2-11-80-71/345; ethics/animal experimentation approval 84-02.04.2013/A164, Landesamt für Natur-, Umwelt- und Verbraucherschutz Nordrhein-Westfalen). Before sampling, animals were anaesthetized with ketamine combined with xylazine (Garcia Montero et al. 2015). Every effort was made to minimize suffering.
- Jing-Dong Jackie Han, Chinese Academy of Sciences, China
© 2021, Sahm et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
N6-methyladenosine (m6A) RNA modification impacts mRNA fate primarily via reader proteins, which dictate processes in development, stress, and disease. Yet little is known about m6A function in Saccharomyces cerevisiae, which occurs solely during early meiosis. Here we perform a multifaceted analysis of the m6A reader protein Pho92/Mrb1. Cross-linking immunoprecipitation analysis reveals that Pho92 associates with the 3’end of meiotic mRNAs in both an m6A-dependent and independent manner. Within cells, Pho92 transitions from the nucleus to the cytoplasm, and associates with translating ribosomes. In the nucleus Pho92 associates with target loci through its interaction with transcriptional elongator Paf1C. Functionally, we show that Pho92 promotes and links protein synthesis to mRNA decay. As such, the Pho92-mediated m6A-mRNA decay is contingent on active translation and the CCR4-NOT complex. We propose that the m6A reader Pho92 is loaded co-transcriptionally to facilitate protein synthesis and subsequent decay of m6A modified transcripts, and thereby promotes meiosis.
Alternative polyadenylation yields many mRNA isoforms whose 3' termini occur disproportionately in clusters within 3' UTRs. Previously, we showed that profiles of poly(A) site usage are regulated by the rate of transcriptional elongation by RNA polymerase (Pol) II (Geisberg et., 2020). Pol II derivatives with slow elongation rates confer an upstream-shifted poly(A) profile, whereas fast Pol II strains confer a downstream-shifted poly(A) profile. Within yeast isoform clusters, these shifts occur steadily from one isoform to the next across nucleotide distances. In contrast, the shift between clusters from the last isoform of one cluster to the first isoform of the next - is much less pronounced, even over large distances. GC content in a region 13-30 nt downstream from isoform clusters correlates with their sensitivity to Pol II elongation rate. In human cells, the upstream shift caused by a slow Pol II mutant also occurs continuously at the nucleotide level within clusters, but not between them. Pol II occupancy increases just downstream of the most speed-sensitive poly(A) sites, suggesting a linkage between reduced elongation rate and cluster formation. These observations suggest that 1) Pol II elongation speed affects the nucleotide-level dwell time allowing polyadenylation to occur, 2) poly(A) site clusters are linked to the local elongation rate and hence do not arise simply by intrinsically imprecise cleavage and polyadenylation of the RNA substrate, 3) DNA sequence elements can affect Pol II elongation and poly(A) profiles, and 4) the cleavage/polyadenylation and Pol II elongation complexes are spatially, and perhaps physically, coupled so that polyadenylation occurs rapidly upon emergence of the nascent RNA from the Pol II elongation complex.