References of "Jovaisaite, Virginija"
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See detailJoint mouse-human phenome-wide association to test gene function and disease risk.
Wang, Xusheng; Pandey, Ashutosh K.; Mulligan, Megan K. et al

in Nature communications (2016), 7

Phenome-wide association is a novel reverse genetic strategy to analyze genome-to-phenome relations in human clinical cohorts. Here we test this approach using a large murine population segregating for ... [more ▼]

Phenome-wide association is a novel reverse genetic strategy to analyze genome-to-phenome relations in human clinical cohorts. Here we test this approach using a large murine population segregating for approximately 5 million sequence variants, and we compare our results to those extracted from a matched analysis of gene variants in a large human cohort. For the mouse cohort, we amassed a deep and broad open-access phenome consisting of approximately 4,500 metabolic, physiological, pharmacological and behavioural traits, and more than 90 independent expression quantitative trait locus (QTL), transcriptome, proteome, metagenome and metabolome data sets--by far the largest coherent phenome for any experimental cohort (www.genenetwork.org). We tested downstream effects of subsets of variants and discovered several novel associations, including a missense mutation in fumarate hydratase that controls variation in the mitochondrial unfolded protein response in both mouse and Caenorhabditis elegans, and missense mutations in Col6a5 that underlies variation in bone mineral density in both mouse and human. [less ▲]

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See detailTwo Conserved Histone Demethylases Regulate Mitochondrial Stress-Induced Longevity.
Merkwirth, Carsten; Jovaisaite, Virginija; Durieux, Jenni et al

in Cell (2016), 165(5), 1209-1223

Across eukaryotic species, mild mitochondrial stress can have beneficial effects on the lifespan of organisms. Mitochondrial dysfunction activates an unfolded protein response (UPR(mt)), a stress ... [more ▼]

Across eukaryotic species, mild mitochondrial stress can have beneficial effects on the lifespan of organisms. Mitochondrial dysfunction activates an unfolded protein response (UPR(mt)), a stress signaling mechanism designed to ensure mitochondrial homeostasis. Perturbation of mitochondria during larval development in C. elegans not only delays aging but also maintains UPR(mt) signaling, suggesting an epigenetic mechanism that modulates both longevity and mitochondrial proteostasis throughout life. We identify the conserved histone lysine demethylases jmjd-1.2/PHF8 and jmjd-3.1/JMJD3 as positive regulators of lifespan in response to mitochondrial dysfunction across species. Reduction of function of the demethylases potently suppresses longevity and UPR(mt) induction, while gain of function is sufficient to extend lifespan in a UPR(mt)-dependent manner. A systems genetics approach in the BXD mouse reference population further indicates conserved roles of the mammalian orthologs in longevity and UPR(mt) signaling. These findings illustrate an evolutionary conserved epigenetic mechanism that determines the rate of aging downstream of mitochondrial perturbations. [less ▲]

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See detailTetracyclines Disturb Mitochondrial Function across Eukaryotic Models: A Call for Caution in Biomedical Research.
Moullan, Norman; Mouchiroud, Laurent; Wang, Xu et al

in Cell reports (2015), 10(10), 1681-1691

In recent years, tetracyclines, such as doxycycline, have become broadly used to control gene expression by virtue of the Tet-on/Tet-off systems. However, the wide range of direct effects of tetracycline ... [more ▼]

In recent years, tetracyclines, such as doxycycline, have become broadly used to control gene expression by virtue of the Tet-on/Tet-off systems. However, the wide range of direct effects of tetracycline use has not been fully appreciated. We show here that these antibiotics induce a mitonuclear protein imbalance through their effects on mitochondrial translation, an effect that likely reflects the evolutionary relationship between mitochondria and proteobacteria. Even at low concentrations, tetracyclines induce mitochondrial proteotoxic stress, leading to changes in nuclear gene expression and altered mitochondrial dynamics and function in commonly used cell types, as well as worms, flies, mice, and plants. Given that tetracyclines are so widely applied in research, scientists should be aware of their potentially confounding effects on experimental results. Furthermore, these results caution against extensive use of tetracyclines in livestock due to potential downstream impacts on the environment and human health. [less ▲]

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See detailMultilayered genetic and omics dissection of mitochondrial activity in a mouse reference population.
Wu, Yibo; Williams, Evan UL; Dubuis, Sebastien et al

in Cell (2014), 158(6), 1415-1430

The manner by which genotype and environment affect complex phenotypes is one of the fundamental questions in biology. In this study, we quantified the transcriptome--a subset of the metabolome--and ... [more ▼]

The manner by which genotype and environment affect complex phenotypes is one of the fundamental questions in biology. In this study, we quantified the transcriptome--a subset of the metabolome--and, using targeted proteomics, quantified a subset of the liver proteome from 40 strains of the BXD mouse genetic reference population on two diverse diets. We discovered dozens of transcript, protein, and metabolite QTLs, several of which linked to metabolic phenotypes. Most prominently, Dhtkd1 was identified as a primary regulator of 2-aminoadipate, explaining variance in fasted glucose and diabetes status in both mice and humans. These integrated molecular profiles also allowed further characterization of complex pathways, particularly the mitochondrial unfolded protein response (UPR(mt)). UPR(mt) shows strikingly variant responses at the transcript and protein level that are remarkably conserved among C. elegans, mice, and humans. Overall, these examples demonstrate the value of an integrated multilayered omics approach to characterize complex metabolic phenotypes. [less ▲]

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