Tissue-specific transcriptome profiling of Drosophila reveals roles for GATA transcription factors in longevity by dietary restriction

Abstract

Dietary restriction (DR) extends animal lifespan, but imposes fitness costs. This phenomenon depends on dietary essential amino acids (EAAs) and TOR signalling, which exert systemic effects. However, the roles of specific tissues and cell-autonomous transcriptional regulators in diverse aspects of the DR phenotype are unknown. Manipulating relevant transcription factors (TFs) specifically in lifespan-limiting tissues may separate the lifespan benefits of DR from the early-life fitness costs. Here, we systematically analyse transcription across organs of Drosophila subjected to DR or low TOR and predict regulatory TFs. We predict and validate roles for the evolutionarily conserved GATA family of TFs, and identify conservation of this signal in mice. Importantly, restricting knockdown of the GATA TF srp to specific fly tissues recapitulated the benefits but not the costs of DR. Together, our data indicate that the GATA TFs mediate effects of dietary amino acids on lifespan, and that by manipulating them in specific tissues it is possible to reap the fitness benefits of EAAs, decoupled from a cost to longevity.

Sex-specific transcriptomic responses to changes in the nutritional environment

“…For example, the ovary-specific dGATAb binds upstream of both yolk protein genes Yp1 and Yp2 [69]. GATA-related motifs have also previously been shown to be enriched in genes showing differential expression in response to DR and rapamycin treatment in female flies [29]. The shared regulation is further supported by the fact that the diet-responsive genes we identify here also overlap significantly with those previously inferred to respond to DRand rapamycin-treatment.…”

“…In order to relate shifts in diet quality to dietary restriction treatments that are widely used in the field, we assessed whether genes in our three categories of diet-dependent regulation overlapped significantly with sets of genes that had previously been shown to change expression in response to dietary restriction and rapamycin in females, analysed separately for brain, thorax, gut, and fat body [29]. We found significant overlap in the majority of comparisons made (Table 3).…”

“…Categories highlighted in orange encompass genes that show an additive effect to diet (D), whereas clusters in blue show interactive effects (DxS). Green rows show both additive and interactive effects (D+DxS) Table 3: Gene overlap between our three categories (D, D×S, D+D×S) and female transcriptomic response to dietary restriction and rapamycin across six different tissues [29].…”

“…Specifically, two evolutionarily conserved signaling pathwaysinsulin and TOR (Target Of Rapamycin)-are thought to regulate longevity in a dietdependent way [21,27,28]. Recent transcriptomic work in female D. melanogaster has further shown that DR and rapamycin treatment (which inhibits amino acid signaling through TOR) elicit similar changes in gene expression [29]. Both responses are mediated by transcription factors in the GATA family, in line with the involvement of these regulators in amino acid signaling and lifespan modulation across eukaryotes [29].…”

Longevity in response to lowered insulin signaling requires glycine N‐methyltransferase‐dependent spermidine production

“…Studies examining the transcriptomic and proteomic changes that occur during aging, or in response to interventions that ameliorate its effects, have revealed several conserved prolongevity processes, including many metabolic changes (Afschar et al, ; Dobson et al, ; Hahn et al, ; Murphy et al, ; Narayan et al, ; Page et al, ; Stout et al, ; Tain et al, ; Teleman, Hietakangas, Sayadian, & Cohen, ). These include carbohydrate metabolism (Afschar et al, ), lipid and fatty acid metabolism (Dobson et al, ; Hahn et al, ; Murphy et al, ; Page et al, ), energy metabolism (Afschar et al, ), and protein and methionine (Met) metabolism (Narayan et al, ; Stout et al, ).…”