References of "Williams, Evan 50039898"
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See detailIntegrative systems analysis identifies genetic and dietary modulators of bile acid homeostasis
Li, Hao; Perino, Alessia; Huang, Qingyao et al

in Cell Metabolism (2022), 34(10), 1594-1610

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See detailPCfun: a hybrid computational framework for systematic characterization of protein complex function
Sharma, Varun; Fossati, Andrea; Ciuffa, Rodolfo et al

in Briefings in Bioinformatics (2022), 23(4), 239

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See detailGCN5 maintains muscle integrity by acetylating YY1 to promote dystrophin expression
Addicks, Gregory; Zhang, Hongbo; Ryu, Dongryeol et al

in Journal of Cell Biology (2022), 221(2),

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See detailThe mouse metallomic landscape of aging and metabolism
Morel, Jean-David; Sauzéat, Lucie; Goeminne, Ludger et al

in Nature Communications (2022), 13(607),

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See detailMultiomic profiling of the liver across diets and age in a diverse mouse population
Williams, Evan UL; Pfister, Niklas; Roy, Suheeta et al

in Cell Systems (2022), 13(1), 43-57

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See detailA platform for experimental precision medicine: The extended BXD mouse family.
Ashbrook, David G.; Arends, Danny; Prins, Pjotr et al

in Cell systems (2021), 12(3), 235-2479

The challenge of precision medicine is to model complex interactions among DNA variants, phenotypes, development, environments, and treatments. We address this challenge by expanding the BXD family of ... [more ▼]

The challenge of precision medicine is to model complex interactions among DNA variants, phenotypes, development, environments, and treatments. We address this challenge by expanding the BXD family of mice to 140 fully isogenic strains, creating a uniquely powerful model for precision medicine. This family segregates for 6 million common DNA variants-a level that exceeds many human populations. Because each member can be replicated, heritable traits can be mapped with high power and precision. Current BXD phenomes are unsurpassed in coverage and include much omics data and thousands of quantitative traits. BXDs can be extended by a single-generation cross to as many as 19,460 isogenic F1 progeny, and this extended BXD family is an effective platform for testing causal modeling and for predictive validation. BXDs are a unique core resource for the field of experimental precision medicine. [less ▲]

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See detailGene-by-environment modulation of lifespan and weight gain in the murine BXD family
Roy, Suheeta; Bou Sleiman, Maroun; Jha, Pooja et al

in Nature Metabolism (2021)

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See detailMolecular pathways behind acquired obesity: Adipose tissue and skeletal muscle multiomics in monozygotic twin pairs discordant for BMI.
van der Kolk, Birgitta W.; Saari, Sina; Lovric, Alen et al

in Cell Reports Medicine (2021), 2(4), 100226

Tissue-specific mechanisms prompting obesity-related development complications in humans remain unclear. We apply multiomics analyses of subcutaneous adipose tissue and skeletal muscle to examine the ... [more ▼]

Tissue-specific mechanisms prompting obesity-related development complications in humans remain unclear. We apply multiomics analyses of subcutaneous adipose tissue and skeletal muscle to examine the effects of acquired obesity among 49 BMI-discordant monozygotic twin pairs. Overall, adipose tissue appears to be more affected by excess body weight than skeletal muscle. In heavier co-twins, we observe a transcriptional pattern of downregulated mitochondrial pathways in both tissues and upregulated inflammatory pathways in adipose tissue. In adipose tissue, heavier co-twins exhibit lower creatine levels; in skeletal muscle, glycolysis- and redox stress-related protein and metabolite levels remain higher. Furthermore, metabolomics analyses in both tissues reveal that several proinflammatory lipids are higher and six of the same lipid derivatives are lower in acquired obesity. Finally, in adipose tissue, but not in skeletal muscle, mitochondrial downregulation and upregulated inflammation are associated with a fatty liver, insulin resistance, and dyslipidemia, suggesting that adipose tissue dominates in acquired obesity. [less ▲]

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See detailStabilizing variable selection and regression
Pfister, Niklas; Williams, Evan UL; Peters, Jonas et al

in Annals of Applied Statistics (2021), 15(3),

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See detailDiagnostics and correction of batch effects in large-scale proteomic studies: a tutorial.
Čuklina, Jelena; Lee, Chloe H.; Williams, Evan UL et al

in Molecular systems biology (2021), 17(8), 10240

Advancements in mass spectrometry-based proteomics have enabled experiments encompassing hundreds of samples. While these large sample sets deliver much-needed statistical power, handling them introduces ... [more ▼]

Advancements in mass spectrometry-based proteomics have enabled experiments encompassing hundreds of samples. While these large sample sets deliver much-needed statistical power, handling them introduces technical variability known as batch effects. Here, we present a step-by-step protocol for the assessment, normalization, and batch correction of proteomic data. We review established methodologies from related fields and describe solutions specific to proteomic challenges, such as ion intensity drift and missing values in quantitative feature matrices. Finally, we compile a set of techniques that enable control of batch effect adjustment quality. We provide an R package, "proBatch", containing functions required for each step of the protocol. We demonstrate the utility of this methodology on five proteomic datasets each encompassing hundreds of samples and consisting of multiple experimental designs. In conclusion, we provide guidelines and tools to make the extraction of true biological signal from large proteomic studies more robust and transparent, ultimately facilitating reliable and reproducible research in clinical proteomics and systems biology. [less ▲]

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See detailSECAT: Quantifying Protein Complex Dynamics across Cell States by Network-Centric Analysis of SEC-SWATH-MS Profiles.
Rosenberger, George; Heusel, Moritz; Bludau, Isabell et al

in Cell systems (2020), 11(6), 589-6078

Protein-protein interactions (PPIs) play critical functional and regulatory roles in cellular processes. They are essential for macromolecular complex formation, which in turn constitutes the basis for ... [more ▼]

Protein-protein interactions (PPIs) play critical functional and regulatory roles in cellular processes. They are essential for macromolecular complex formation, which in turn constitutes the basis for protein interaction networks that determine the functional state of a cell. We and others have previously shown that chromatographic fractionation of native protein complexes in combination with bottom-up mass spectrometric analysis of consecutive fractions supports the multiplexed characterization and detection of state-specific changes of protein complexes. In this study, we extend co-fractionation and mass spectrometric data analysis to perform quantitative, network-based studies of proteome organization, via the size-exclusion chromatography algorithmic toolkit (SECAT). This framework explicitly accounts for the dynamic nature and rewiring of protein complexes across multiple cell states and samples, thus, elucidating molecular mechanisms that are differentially implemented across different experimental settings. Systematic analysis of multiple datasets shows that SECAT represents a highly scalable and effective methodology to assess condition/state-specific protein-network state. A record of this paper's transparent peer review process is included in the Supplemental Information. [less ▲]

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See detailBody weight and high-fat diet are associated with epigenetic aging in female members of the BXD murine family.
Sandoval-Sierra, Jose Vladimir; Helbing, Alexandra H. B.; Williams, Evan UL et al

in Aging cell (2020), 19(9), 13207

DNA methylation (DNAm) is shaped by genetic and environmental factors and modulated by aging. Here, we examine interrelations between epigenetic aging, body weight (BW), and life span in 12 isogenic ... [more ▼]

DNA methylation (DNAm) is shaped by genetic and environmental factors and modulated by aging. Here, we examine interrelations between epigenetic aging, body weight (BW), and life span in 12 isogenic strains from the BXD family of mice that exhibit over twofold variation in longevity. Genome-wide DNAm was assayed in 70 liver specimens from predominantly female cases, 6-25 months old, that were maintained on normal chow or high-fat diet (HFD). We defined subsets of CpG regions associated with age, BW at young adulthood, and strain-by-diet-dependent life span. These age-associated differentially methylated CpG regions (age-DMRs) featured distinct genomic characteristics, with DNAm gains over time occurring in sites such as promoters and exons that have high CpG density and low average methylation. CpG regions associated with BW were enriched in introns, tended to have lower methylation in mice with higher BW, and were inversely correlated with gene expression (i.e., higher mRNA levels in mice with higher BW). CpG regions associated with life span were linked to genes involved in life span modulation, including the telomerase reverse transcriptase gene, Tert, which had both lower methylation and higher expression in long-lived strains. An epigenetic clock defined from age-DMRs revealed accelerated aging in mice belonging to strains with shorter life spans. Both higher BW and the HFD were associated with accelerated epigenetic aging. Our results highlight the age-accelerating effect of heavier BW. Furthermore, we demonstrate that the measure of epigenetic aging derived from age-DMRs can predict genotype and diet-induced differences in life span among female BXD members. [less ▲]

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See detailA Conserved Mito-Cytosolic Translational Balance Links Two Longevity Pathways.
Molenaars, Marte; Janssens, Georges E.; Williams, Evan UL et al

in Cell metabolism (2020), 31(3), 549-5637

Slowing down translation in either the cytosol or the mitochondria is a conserved longevity mechanism. Here, we found a non-interventional natural correlation of mitochondrial and cytosolic ribosomal ... [more ▼]

Slowing down translation in either the cytosol or the mitochondria is a conserved longevity mechanism. Here, we found a non-interventional natural correlation of mitochondrial and cytosolic ribosomal proteins (RPs) in mouse population genetics, suggesting a translational balance. Inhibiting mitochondrial translation in C. elegans through mrps-5 RNAi repressed cytosolic translation. Transcriptomics integrated with proteomics revealed that this inhibition specifically reduced translational efficiency of mRNAs required in growth pathways while increasing stress response mRNAs. The repression of cytosolic translation and extension of lifespan from mrps-5 RNAi were dependent on atf-5/ATF4 and independent from metabolic phenotypes. We found the translational balance to be conserved in mammalian cells upon inhibiting mitochondrial translation pharmacologically with doxycycline. Lastly, extending this in vivo, doxycycline repressed cytosolic translation in the livers of germ-free mice. These data demonstrate that inhibiting mitochondrial translation initiates an atf-5/ATF4-dependent cascade leading to coordinated repression of cytosolic translation, which could be targeted to promote longevity. [less ▲]

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See detailMitochondrial translation and dynamics synergistically extend lifespan in C. elegans through HLH-30.
Liu, Yasmine J.; McIntyre, Rebecca L.; Janssens, Georges E. et al

in The Journal of cell biology (2020), 219(6),

Mitochondrial form and function are closely interlinked in homeostasis and aging. Inhibiting mitochondrial translation is known to increase lifespan in C. elegans, and is accompanied by a fragmented ... [more ▼]

Mitochondrial form and function are closely interlinked in homeostasis and aging. Inhibiting mitochondrial translation is known to increase lifespan in C. elegans, and is accompanied by a fragmented mitochondrial network. However, whether this link between mitochondrial translation and morphology is causal in longevity remains uncharacterized. Here, we show in C. elegans that disrupting mitochondrial network homeostasis by blocking fission or fusion synergizes with reduced mitochondrial translation to prolong lifespan and stimulate stress response such as the mitochondrial unfolded protein response, UPRMT. Conversely, immobilizing the mitochondrial network through a simultaneous disruption of fission and fusion abrogates the lifespan increase induced by mitochondrial translation inhibition. Furthermore, we find that the synergistic effect of inhibiting both mitochondrial translation and dynamics on lifespan, despite stimulating UPRMT, does not require it. Instead, this lifespan-extending synergy is exclusively dependent on the lysosome biogenesis and autophagy transcription factor HLH-30/TFEB. Altogether, our study reveals the mechanistic crosstalk between mitochondrial translation, mitochondrial dynamics, and lysosomal signaling in regulating longevity. [less ▲]

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See detailMild inborn errors of metabolism in commonly used inbred mouse strains.
Leandro, Joao; Violante, Sara; Argmann, Carmen A. et al

in Molecular Genetics and Metabolism (2019), 126(4), 388-396

Inbred mouse strains are a cornerstone of translational research but paradoxically many strains carry mild inborn errors of metabolism. For example, alpha-aminoadipic acidemia and branched-chain ketoacid ... [more ▼]

Inbred mouse strains are a cornerstone of translational research but paradoxically many strains carry mild inborn errors of metabolism. For example, alpha-aminoadipic acidemia and branched-chain ketoacid dehydrogenase deficiency are known in C57BL/6J mice. Using RNA sequencing, we now reveal the causal variants in Dhtkd1 and Bckdhb, and the molecular mechanism underlying these metabolic defects. C57BL/6J mice have decreased Dhtkd1 mRNA expression due to a solitary long terminal repeat (LTR) in intron 4 of Dhtkd1. This LTR harbors an alternate splice donor site leading to a partial splicing defect and as a consequence decreased total and functional Dhtkd1 mRNA, decreased DHTKD1 protein and alpha-aminoadipic acidemia. Similarly, C57BL/6J mice have decreased Bckdhb mRNA expression due to an LTR retrotransposon in intron 1 of Bckdhb. This transposable element encodes an alternative exon 1 causing aberrant splicing, decreased total and functional Bckdhb mRNA and decreased BCKDHB protein. Using a targeted metabolomics screen, we also reveal elevated plasma C5-carnitine in 129 substrains. This biochemical phenotype resembles isovaleric acidemia and is caused by an exonic splice mutation in Ivd leading to partial skipping of exon 10 and IVD protein deficiency. In summary, this study identifies three causal variants underlying mild inborn errors of metabolism in commonly used inbred mouse strains. [less ▲]

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See detailJCAD: from systems genetics identification to the experimental validation of a coronary artery disease risk locus.
Williams, Evan UL; Stein, Sokrates

in European heart journal (2019), 40(29), 2409-2412

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See detailMulti-omic measurements of heterogeneity in HeLa cells across laboratories.
Liu, Yansheng; Mi, Yang; Mueller, Torsten et al

in Nature biotechnology (2019), 37(3), 314-322

Reproducibility in research can be compromised by both biological and technical variation, but most of the focus is on removing the latter. Here we investigate the effects of biological variation in HeLa ... [more ▼]

Reproducibility in research can be compromised by both biological and technical variation, but most of the focus is on removing the latter. Here we investigate the effects of biological variation in HeLa cell lines using a systems-wide approach. We determine the degree of molecular and phenotypic variability across 14 stock HeLa samples from 13 international laboratories. We cultured cells in uniform conditions and profiled genome-wide copy numbers, mRNAs, proteins and protein turnover rates in each cell line. We discovered substantial heterogeneity between HeLa variants, especially between lines of the CCL2 and Kyoto varieties, and observed progressive divergence within a specific cell line over 50 successive passages. Genomic variability has a complex, nonlinear effect on transcriptome, proteome and protein turnover profiles, and proteotype patterns explain the varying phenotypic response of different cell lines to Salmonella infection. These findings have implications for the interpretation and reproducibility of research results obtained from human cultured cells. [less ▲]

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See detailA new class of protein biomarkers based on subcellular distribution: application to a mouse liver cancer model.
Sajic, Tatjana; Ciuffa, Rodolfo; Lemos, Vera et al

in Scientific reports (2019), 9(1), 6913

To-date, most proteomic studies aimed at discovering tissue-based cancer biomarkers have compared the quantity of selected proteins between case and control groups. However, proteins generally function in ... [more ▼]

To-date, most proteomic studies aimed at discovering tissue-based cancer biomarkers have compared the quantity of selected proteins between case and control groups. However, proteins generally function in association with other proteins to form modules localized in particular subcellular compartments in specialized cell types and tissues. Sub-cellular mislocalization of proteins has in fact been detected as a key feature in a variety of cancer cells. Here, we describe a strategy for tissue-biomarker detection based on a mitochondrial fold enrichment (mtFE) score, which is sensitive to protein abundance changes as well as changes in subcellular distribution between mitochondria and cytosol. The mtFE score integrates protein abundance data from total cellular lysates and mitochondria-enriched fractions, and provides novel information for the classification of cancer samples that is not necessarily apparent from conventional abundance measurements alone. We apply this new strategy to a panel of wild-type and mutant mice with a liver-specific gene deletion of Liver receptor homolog 1 (Lrh-1(hep-/-)), with both lines containing control individuals as well as individuals with liver cancer induced by diethylnitrosamine (DEN). Lrh-1 gene deletion attenuates cancer cell metabolism in hepatocytes through mitochondrial glutamine processing. We show that proteome changes based on mtFE scores outperform protein abundance measurements in discriminating DEN-induced liver cancer from healthy liver tissue, and are uniquely robust against genetic perturbation. We validate the capacity of selected proteins with informative mtFE scores to indicate hepatic malignant changes in two independent mouse models of hepatocellular carcinoma (HCC), thus demonstrating the robustness of this new approach to biomarker research. Overall, the method provides a novel, sensitive approach to cancer biomarker discovery that considers contextual information of tested proteins. [less ▲]

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See detailDiet modulates cecum bacterial diversity and physiological phenotypes across the BXD mouse genetic reference population.
Perez-Munoz, Maria Elisa; McKnite, Autumn M.; Williams, Evan UL et al

in PloS one (2019), 14(10), 0224100

The BXD family has become one of the preeminent genetic reference populations to understand the genetic and environmental control of phenotypic variation. Here we evaluate the responses to different ... [more ▼]

The BXD family has become one of the preeminent genetic reference populations to understand the genetic and environmental control of phenotypic variation. Here we evaluate the responses to different levels of fat in the diet using both chow diet (CD, 13-18% fat) and a high-fat diet (HFD, 45-60% fat). We studied cohorts of BXD strains, both inbred parents C57BL/6J and DBA/2J (commonly known as B6 and D2, respectively), as well as B6D2 and D2B6 reciprocal F1 hybrids. The comparative impact of genetic and dietary factors was analyzed by profiling a range of phenotypes, most prominently their cecum bacterial composition. The parents of the BXDs and F1 hybrids express limited differences in terms of weight and body fat gain on CD. In contrast, the strain differences on HFD are substantial for percent body fat, with DBA/2J accumulating 12.5% more fat than C57BL/6J (P < 0.0001). The F1 hybrids born to DBA/2J dams (D2B6F1) have 10.6% more body fat (P < 0.001) than those born to C57BL/6J dams. Sequence analysis of the cecum microbiota reveals important differences in bacterial composition among BXD family members with a substantial shift in composition caused by HFD. Relative to CD, the HFD induces a decline in diversity at the phylum level with a substantial increase in Firmicutes (+13.8%) and a reduction in Actinobacteria (-7.9%). In the majority of BXD strains, the HFD also increases cecal sIgA (P < 0.0001)-an important component of the adaptive immunity response against microbial pathogens. Host genetics modulates variation in cecum bacterial composition at the genus level in CD, with significant quantitative trait loci (QTLs) for Oscillibacter mapped to Chr 3 (18.7-19.2 Mb, LRS = 21.4) and for Bifidobacterium mapped to Chr 6 (89.21-89.37 Mb, LRS = 19.4). Introduction of HFD served as an environmental suppressor of these QTLs due to a reduction in the contribution of both genera (P < 0.001). Relations among liver metabolites and cecum bacterial composition were predominant in CD cohort, but these correlations do not persist following the shift to HFD. Overall, these findings demonstrate the important impact of environmental/dietary manipulation on the relationships between host genetics, gastrointestinal bacterial composition, immunological parameters, and metabolites-knowledge that will help in the understanding of the causal sources of metabolic disorders. [less ▲]

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See detailGenetic cartography of longevity in humans and mice: Current landscape and horizons.
Hook, Michael; Roy, Suheeta; Williams, Evan UL et al

in Biochimica et biophysica acta. Molecular basis of disease (2018), 1864(9 Pt A), 2718-2732

Aging is a complex and highly variable process. Heritability of longevity among humans and other species is low, and this finding has given rise to the idea that it may be futile to search for DNA ... [more ▼]

Aging is a complex and highly variable process. Heritability of longevity among humans and other species is low, and this finding has given rise to the idea that it may be futile to search for DNA variants that modulate aging. We argue that the problem in mapping longevity genes is mainly one of low power and the genetic and environmental complexity of aging. In this review we highlight progress made in mapping genes and molecular networks associated with longevity, paying special attention to work in mice and humans. We summarize 40years of linkage studies using murine cohorts and 15years of studies in human populations that have exploited candidate gene and genome-wide association methods. A small but growing number of gene variants contribute to known longevity mechanisms, but a much larger set have unknown functions. We outline these and other challenges and suggest some possible solutions, including more intense collaboration between research communities that use model organisms and human cohorts. Once hundreds of gene variants have been linked to differences in longevity in mammals, it will become feasible to systematically explore gene-by-environmental interactions, dissect mechanisms with more assurance, and evaluate the roles of epistasis and epigenetics in aging. A deeper understanding of complex networks-genetic, cellular, physiological, and social-should position us well to improve healthspan. [less ▲]

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