Title: Lifespan regulation by the evolutionarily conserved transcription factor Hth/Meis2
Directors: Frédéric MARMIGERE & Xiaotao LI
Discipline: Biology
Status: Incubating Project
Starting date: 2020
Directors
The lab of Xiaotao Li (East China Normal University) and the Institute of Functional Genomic (Ecole Normale Supérieure de Lyon) are contributing with their complimentary expertise to initiate a novel research program on ageing and the genetic of lifespan regulation.
Summary
Aging is characterised by a progressive loss of physiological integrity and has been defined by nine hallmarks including genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. The biochemical processes and genetic pathways governing aging and regulating lifespan are conserved from yeasts to worms, flies and mammals. These highly conserved mechanisms mainly involve the insulin/Insulin-like (IIS) and the TOR (Target Of Rapamycin) signalling pathways. Therefore, mutations, downregulation or overexpression of the different genes involved in these pathways consistently accelerate or slow down aging processes, eventually leading to extended or shortened lifespan across species.
Very few transcription factors (TFs) are known to regulate lifespan through conserved mechanisms. Among them, DAF-16/FoxO TF plays an essential and pivotal role and is one of the few genes that have been consistently associated with longevity in all studied animals models. Besides transcriptional regulation of the gene, posttranscriptional modifications modulate DAF-16/FoxO activities by influencing its shuttling between the cytoplasm and the nucleus. Nuclear FoxO binds DNA and regulates the expression of many pro-longevity target genes including genes participating to autophagy, whereas FoxO sequestration in the cytoplasm inhibits its anti-aging activities. FoxO appears thus as a central hub directly and indirectly regulating most of ageing hallmarks.
In C. elegans, Unc-62 is another TF linked to lifespan regulation with opposing effects to DAF-16/FoxO. Orthologs of Unc-62 are highly conserved in the animal kingdom and corresponds to Homothorax (Hth) and Myeloid-Ecotropic-Integration-Site (Meis) in Drosophila and mammals respectively. Unc-62 downregulation in adult worms extends lifespan and DAF-16/FoxO activity, but whether Unc-62 is part of the conserved genes network regulating aging and lifespan is not demonstrated, and the precise mechanism by which this effect is mediated is not elucidated.
In this project, we aim at establishing Hth/Meis2 as part of the conserved molecular processes governing aging processes using two model organisms, Drosophila and mice. Our data indicate that Hth/Meis2 exerts pro-aging activity during adult life in these two model species. Decreasing or suppressing their expression only during adult life extends lifespan both in Drosophila and mice. Given that preserved autophagy and autophagy-regulated proteostasis are hallmarks in model organisms involving DAF-16/FoxO activities, including food restriction and genetically modified model organisms of longevity, our goal is to demonstrate that autophagy is also preserved as a consequence of Hth/Meis2 downregulation in these two new models.