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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 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 detailGenetic Regulation of Plasma Lipid Species and Their Association with Metabolic Phenotypes.
Jha, Pooja; McDevitt, Molly T.; Halilbasic, Emina et al

in Cell systems (2018), 6(6), 709-7216

The genetic regulation and physiological impact of most lipid species are unexplored. Here, we profiled 129 plasma lipid species across 49 strains of the BXD mouse genetic reference population fed either ... [more ▼]

The genetic regulation and physiological impact of most lipid species are unexplored. Here, we profiled 129 plasma lipid species across 49 strains of the BXD mouse genetic reference population fed either chow or a high-fat diet. By integrating these data with genomics and phenomics datasets, we elucidated genes by environment (diet) interactions that regulate systemic metabolism. We found quantitative trait loci (QTLs) for approximately 94% of the lipids measured. Several QTLs harbored genes associated with blood lipid levels and abnormal lipid metabolism in human genome-wide association studies. Lipid species from different classes provided signatures of metabolic health, including seven plasma triglyceride species that associated with either healthy or fatty liver. This observation was further validated in an independent mouse model of non-alcoholic fatty liver disease (NAFLD) and in plasma from NAFLD patients. This work provides a resource to identify plausible genes regulating the measured lipid species and their association with metabolic traits. [less ▲]

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See detailSystems Analyses Reveal Physiological Roles and Genetic Regulators of Liver Lipid Species.
Jha, Pooja; McDevitt, Molly T.; Gupta, Rahul et al

in Cell systems (2018), 6(6), 722-7336

The genetics of individual lipid species and their relevance in disease is largely unresolved. We profiled a subset of storage, signaling, membrane, and mitochondrial liver lipids across 385 mice from 47 ... [more ▼]

The genetics of individual lipid species and their relevance in disease is largely unresolved. We profiled a subset of storage, signaling, membrane, and mitochondrial liver lipids across 385 mice from 47 strains of the BXD mouse population fed chow or high-fat diet and integrated these data with complementary multi-omics datasets. We identified several lipid species and lipid clusters with specific phenotypic and molecular signatures and, in particular, cardiolipin species with signatures of healthy and fatty liver. Genetic analyses revealed quantitative trait loci for 68% of the lipids (lQTL). By multi-layered omics analyses, we show the reliability of lQTLs to uncover candidate genes that can regulate the levels of lipid species. Additionally, we identified lQTLs that mapped to genes associated with abnormal lipid metabolism in human GWASs. This work provides a foundation and resource for understanding the genetic regulation and physiological significance of lipid species. [less ▲]

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See detailResolving the Combinatorial Complexity of Smad Protein Complex Formation and Its Link to Gene Expression.
Lucarelli, Philippe UL; Schilling, Marcel; Kreutz, Clemens et al

in Cell Systems (2017)

Upon stimulation of cells with transforming growth factor beta (TGF-beta), Smad proteins form trimeric complexes and activate a broad spectrum of target genes. It remains unresolved which of the possible ... [more ▼]

Upon stimulation of cells with transforming growth factor beta (TGF-beta), Smad proteins form trimeric complexes and activate a broad spectrum of target genes. It remains unresolved which of the possible Smad complexes are formed in cellular contexts and how these contribute to gene expression. By combining quantitative mass spectrometry with a computational selection strategy, we predict and provide experimental evidence for the three most relevant Smad complexes in the mouse hepatoma cell line Hepa1-6. Utilizing dynamic pathway modeling, we specify the contribution of each Smad complex to the expression of representative Smad target genes, and show that these contributions are conserved in human hepatoma cell lines and primary hepatocytes. We predict, based on gene expression data of patient samples, increased amounts of Smad2/3/4 proteins and Smad2 phosphorylation as hallmarks of hepatocellular carcinoma and experimentally verify this prediction. Our findings demonstrate that modeling approaches can disentangle the complexity of transcription factor complex formation and its impact on gene expression. [less ▲]

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