Biology subjects

Atlan, T.

Publications and source records attributed to Atlan, T..

4 recordsLinked to original sources

bioRxiv2024

The cGAS-STING pathway is an in vivo modifier of genomic instability syndromes

Mutations in genes involved in DNA damage repair (DDR) often lead to premature aging syndromes. While recent evidence suggests that inflammation, alongside mutation accumulation and cell death, may drive disease phenotypes, its precise contribution to in vivo pathophysiology remains unclear. Here, by modeling Ataxia Telangiectasia (A-T) and Bloom Syndrome in the African turquoise killifish (N. furzeri), we replicate key phenotypes of DDR syndromes, including infertility, cytoplasmic DNA fragments, and reduced lifespan. The link between DDR defects and inflammation is attributed to the activation of the cGAS-STING pathway and interferon signaling by cytoplasmic DNA. Accordingly, mutating cGAS partially rescues germline defects and senescence in A-T fish. Double mutants also display reversal of telomere abnormalities and suppression of transposable elements, underscoring cGASs non-canonical role as a DDR inhibitor. Our findings emphasize the role of interferon signaling in A-T pathology and identify the cGAS-STING pathway as a potential therapeutic target for genomic instability syndromes.

genetics↗

bioRxiv2023

The germline regulates longevity and somatic repair in a sex-specific manner

Classical evolutionary theories propose tradeoffs between reproduction, damage repair, and lifespan. However, the specific role of the germline in shaping vertebrate aging remains largely unknown. Here, we use the turquoise killifish (N. furzeri) to genetically arrest germline development at discrete stages, and examine how different modes of infertility impact life-history. We first construct a comprehensive single-cell gonadal atlas, providing cell-type-specific markers for downstream phenotypic analysis. Next, we show that germline depletion - but not arresting germline differentiation - enhances damage repair in female killifish. Conversely, germline-depleted males instead showed an extension in lifespan and rejuvenated metabolic functions. Through further transcriptomic analysis, we highlight enrichment of pro-longevity pathways and genes in germline-depleted male killifish and demonstrate functional conservation of how these factors may regulate longevity in germline-depleted C. elegans. Our results therefore demonstrate that different germline manipulation paradigms can yield pronounced sexually dimorphic phenotypes, implying alternative responses to classical evolutionary tradeoffs.

genetics↗

bioRxiv2023

Exploring life-long tissue homeostasis through lineage tracing and cell transplantation

The antagonistic pleiotropy theory of aging predicts functional trade-offs between early-life and late-life fitness. However, empirical evidence for these trade-offs in vertebrates remains scarce, particularly in the context of ecologically relevant life histories. Here, we identify vestigial-like 3 (vgll3), a transcription cofactor previously linked with age at maturity in humans and Atlantic salmon through GWAS studies, as an antagonistically pleiotropic gene in turquoise killifish (Nothobranchius furzeri). By disrupting two conserved vgll3 isoforms, we show that reduction of vgll3, in an isoform- or dose-dependent manner, accelerated male growth and reproductive development. This indicates that vgll3 regulates sexual maturity. However, early-life benefits come at a late-life cost, as older mutant males with a disrupted long isoform develop melanoma-like tumors, validated via transplantation into immunodeficient rag2 models, and exhibit increased age-related mortality rate. These findings highlight vgll3 as a key regulator of vertebrate life-history trade-offs, balancing early-life fitness with late-life disease risks.

genetics↗

bioRxiv2022

Sex-specific regulation of metabolic health and vertebrate lifespan by AMP biosynthesis

Energy homeostasis is disrupted with age, which then fuels multiple age-related pathologies. The AMP-activated protein kinase (AMPK) is the primary sensor of cellular energy in eukaryotes. However, the genetic regulation of vertebrate aging by AMPK remains poorly understood. Here, we manipulate energy levels in the turquoise killifish by mutating APRT, a key enzyme in AMP biosynthesis. These manipulations produced a male-specific lifespan extension and restored metabolic plasticity. Exploring the observed sex differences using an integrated omics approach implicated the mitochondria as an important player. Mechanistically, APRT regulated mitochondrial functions and AMPK activity, mimicking energy starvation in heterozygous cells. A fasting-like state was also detected, particularly in heterozygous males, which leads to resistance to high-fat diet. Finally, life-long intermittent fasting eliminated the male-specific longevity benefits mediated by the APRT mutation. These observations identify the AMP/AMPK axis as a sex-specific regulator of vertebrate longevity and metabolic health.

genetics↗