References of "Williams, Evan 50039898"
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See detailResources for Systems Genetics.
Williams, Robert W.; Williams, Evan UL

in Methods in Molecular Biology (2017), 1488

A key characteristic of systems genetics is its reliance on populations that vary to a greater or lesser degree in genetic complexity-from highly admixed populations such as the Collaborative Cross and ... [more ▼]

A key characteristic of systems genetics is its reliance on populations that vary to a greater or lesser degree in genetic complexity-from highly admixed populations such as the Collaborative Cross and Diversity Outcross to relatively simple crosses such as sets of consomic strains and reduced complexity crosses. This protocol is intended to help investigators make more informed decisions about choices of resources given different types of questions. We consider factors such as costs, availability, and ease of breeding for common scenarios. In general, we recommend using complementary resources and minimizing depth of resampling of any given genome or strain. [less ▲]

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See detailSystematic proteome and proteostasis profiling in human Trisomy 21 fibroblast cells.
Liu, Yansheng; Borel, Christelle; Li, Li et al

in Nature communications (2017), 8(1), 1212

Down syndrome (DS) is mostly caused by a trisomy of the entire Chromosome 21 (Trisomy 21, T21). Here, we use SWATH mass spectrometry to quantify protein abundance and protein turnover in fibroblasts from ... [more ▼]

Down syndrome (DS) is mostly caused by a trisomy of the entire Chromosome 21 (Trisomy 21, T21). Here, we use SWATH mass spectrometry to quantify protein abundance and protein turnover in fibroblasts from a monozygotic twin pair discordant for T21, and to profile protein expression in 11 unrelated DS individuals and matched controls. The integration of the steady-state and turnover proteomic data indicates that protein-specific degradation of members of stoichiometric complexes is a major determinant of T21 gene dosage outcome, both within and between individuals. This effect is not apparent from genomic and transcriptomic data. The data also reveal that T21 results in extensive proteome remodeling, affecting proteins encoded by all chromosomes. Finally, we find broad, organelle-specific post-transcriptional effects such as significant downregulation of the mitochondrial proteome contributing to T21 hallmarks. Overall, we provide a valuable proteomic resource to understand the origin of DS phenotypic manifestations. [less ▲]

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See detailApplication of SWATH Proteomics to Mouse Biology.
Wu, Yibo; Williams, Evan UL; Aebersold, Ruedi

in Current protocols in mouse biology (2017), 7(2), 130-143

The quantitative measurement of the proteome has been shown to yield new insights into physiology and cell biology that cannot be determined from the genome and transcriptome because the quantitative ... [more ▼]

The quantitative measurement of the proteome has been shown to yield new insights into physiology and cell biology that cannot be determined from the genome and transcriptome because the quantitative relationship between transcriptome and proteome is complex. MS-based proteomics techniques, such as SWATH-MS, have recently advanced to the point at which they may be reliably applied by biologists who are not specialists in mass spectrometry. Here we provide standard protocols for preparation of tissue samples for input into the SWATH-MS analytical pipeline. These protocols are designed for high-throughput processing of tissues with >/=5 mg of sample available for analysis. Studies with extremely limited amounts of tissue should consider PCT-SWATH. An experienced single user should be able to process 48 samples per day for injection into the mass spectrometer, or up to 144 samples a week. The machine time necessary for running these samples with SWATH is approximately 1.5 hr per sample. Data acquisition protocols are also provided. (c) 2017 by John Wiley & Sons, Inc. [less ▲]

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See detailSystems proteomics of liver mitochondria function.
Williams, Evan UL; Wu, Yibo; Jha, Pooja et al

in Science (2016), 352(6291), 0189

Recent improvements in quantitative proteomics approaches, including Sequential Window Acquisition of all Theoretical Mass Spectra (SWATH-MS), permit reproducible large-scale protein measurements across ... [more ▼]

Recent improvements in quantitative proteomics approaches, including Sequential Window Acquisition of all Theoretical Mass Spectra (SWATH-MS), permit reproducible large-scale protein measurements across diverse cohorts. Together with genomics, transcriptomics, and other technologies, transomic data sets can be generated that permit detailed analyses across broad molecular interaction networks. Here, we examine mitochondrial links to liver metabolism through the genome, transcriptome, proteome, and metabolome of 386 individuals in the BXD mouse reference population. Several links were validated between genetic variants toward transcripts, proteins, metabolites, and phenotypes. Among these, sequence variants in Cox7a2l alter its protein's activity, which in turn leads to downstream differences in mitochondrial supercomplex formation. This data set demonstrates that the proteome can now be quantified comprehensively, serving as a key complement to transcriptomics, genomics, and metabolomics--a combination moving us forward in complex trait analysis. [less ▲]

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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 detailUrolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents.
Ryu, Dongryeol; Mouchiroud, Laurent; Andreux, Penelope A. et al

in Nature medicine (2016), 22(8), 879-88

The biological effects of urolithins remain poorly characterized, despite wide-spread human exposure via the dietary consumption of their metabolic precursors, the ellagitannins, which are found in the ... [more ▼]

The biological effects of urolithins remain poorly characterized, despite wide-spread human exposure via the dietary consumption of their metabolic precursors, the ellagitannins, which are found in the pomegranate fruit, as well as in nuts and berries. We identified urolithin A (UA) as a first-in-class natural compound that induces mitophagy both in vitro and in vivo following oral consumption. In C. elegans, UA prevented the accumulation of dysfunctional mitochondria with age and extended lifespan. Likewise, UA prolonged normal activity during aging in C. elegans, including mobility and pharyngeal pumping, while maintaining mitochondrial respiratory capacity. These effects translated to rodents, where UA improved exercise capacity in two different mouse models of age-related decline of muscle function, as well as in young rats. Our findings highlight the health benefits of urolithin A and its potential application in strategies to improve mitochondrial and muscle function. [less ▲]

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See detailThe Movement Tracker: A Flexible System for Automated Movement Analysis in Invertebrate Model Organisms.
Mouchiroud, Laurent; Sorrentino, Vincenzo; Williams, Evan UL et al

in Current protocols in neuroscience (2016), 77

Phenotyping strategies in simple model organisms such as D. melanogaster and C. elegans are often broadly limited to growth, aging, and fitness. Recently, a number of physical setups and video tracking ... [more ▼]

Phenotyping strategies in simple model organisms such as D. melanogaster and C. elegans are often broadly limited to growth, aging, and fitness. Recently, a number of physical setups and video tracking software suites have been developed to allow for accurate, quantitative, and high-throughput analysis of movement in flies and worms. However, many of these systems require precise experimental setups and/or fixed recording formats. We report here an update to the Parallel Worm Tracker software, which we termed the Movement Tracker. The Movement Tracker allows variable experimental setups to provide cross-platform automated processing of a variety of movement characteristics in both worms and flies and permits the use of simple physical setups that can be readily implemented in any laboratory. This software allows high-throughput processing capabilities and high levels of flexibility in video analysis, providing quantitative movement data on C. elegans and D. melanogaster in a variety of different conditions. (c) 2016 by John Wiley & Sons, Inc. [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 detailThe Convergence of Systems and Reductionist Approaches in Complex Trait Analysis.
Williams, Evan UL; Auwerx, Johan

in Cell (2015), 162(1), 23-32

Research into the genetic and environmental factors behind complex trait variation has traditionally been segregated into distinct scientific camps. The reductionist approach aims to decrypt phenotypic ... [more ▼]

Research into the genetic and environmental factors behind complex trait variation has traditionally been segregated into distinct scientific camps. The reductionist approach aims to decrypt phenotypic variability bit by bit, founded on the underlying hypothesis that genome-to-phenome relations are largely constructed from the additive effects of their molecular players. In contrast, the systems approach aims to examine large-scale interactions of many components simultaneously, on the premise that interactions in gene networks can be both linear and non-linear. Both approaches are complementary, and they are becoming increasingly intertwined due to developments in gene editing tools, omics technologies, and population resources. Together, these strategies are beginning to drive the next era in complex trait research, paving the way to improve agriculture and toward more personalized medicine. [less ▲]

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See detailEvidence for a direct effect of the NAD+ precursor acipimox on muscle mitochondrial function in humans.
van de Weijer, Tineke; Phielix, Esther; Bilet, Lena et al

in Diabetes (2015), 64(4), 1193-201

Recent preclinical studies showed the potential of nicotinamide adenine dinucleotide (NAD(+)) precursors to increase oxidative phosphorylation and improve metabolic health, but human data are lacking. We ... [more ▼]

Recent preclinical studies showed the potential of nicotinamide adenine dinucleotide (NAD(+)) precursors to increase oxidative phosphorylation and improve metabolic health, but human data are lacking. We hypothesize that the nicotinic acid derivative acipimox, an NAD(+) precursor, would directly affect mitochondrial function independent of reductions in nonesterified fatty acid (NEFA) concentrations. In a multicenter randomized crossover trial, 21 patients with type 2 diabetes (age 57.7 +/- 1.1 years, BMI 33.4 +/- 0.8 kg/m(2)) received either placebo or acipimox 250 mg three times daily dosage for 2 weeks. Acipimox treatment increased plasma NEFA levels (759 +/- 44 vs. 1,135 +/- 97 mumol/L for placebo vs. acipimox, P < 0.01) owing to a previously described rebound effect. As a result, skeletal muscle lipid content increased and insulin sensitivity decreased. Despite the elevated plasma NEFA levels, ex vivo mitochondrial respiration in skeletal muscle increased. Subsequently, we showed that acipimox treatment resulted in a robust elevation in expression of nuclear-encoded mitochondrial gene sets and a mitonuclear protein imbalance, which may indicate activation of the mitochondrial unfolded protein response. Further studies in C2C12 myotubes confirmed a direct effect of acipimox on NAD(+) levels, mitonuclear protein imbalance, and mitochondrial oxidative capacity. To the best of our knowledge, this study is the first to demonstrate that NAD(+) boosters can also directly affect skeletal muscle mitochondrial function in humans. [less ▲]

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See detailAn evolutionarily conserved role for the aryl hydrocarbon receptor in the regulation of movement.
Williams, Evan UL; Mouchiroud, Laurent; Frochaux, Michael et al

in PLoS genetics (2014), 10(9), 1004673

The BXD genetic reference population is a recombinant inbred panel descended from crosses between the C57BL/6 (B6) and DBA/2 (D2) strains of mice, which segregate for about 5 million sequence variants ... [more ▼]

The BXD genetic reference population is a recombinant inbred panel descended from crosses between the C57BL/6 (B6) and DBA/2 (D2) strains of mice, which segregate for about 5 million sequence variants. Recently, some of these variants have been established with effects on general metabolic phenotypes such as glucose response and bone strength. Here we phenotype 43 BXD strains and observe they have large variation (-5-fold) in their spontaneous activity during waking hours. QTL analyses indicate that -40% of this variance is attributable to a narrow locus containing the aryl hydrocarbon receptor (Ahr), a basic helix-loop-helix transcription factor with well-established roles in development and xenobiotic metabolism. Strains with the D2 allele of Ahr have reduced gene expression compared to those with the B6 allele, and have significantly higher spontaneous activity. This effect was also observed in B6 mice with a congenic D2 Ahr interval, and in B6 mice with a humanized AHR allele which, like the D2 allele, is expressed much less and has less enzymatic activity than the B6 allele. Ahr is highly conserved in invertebrates, and strikingly inhibition of its orthologs in D. melanogaster and C. elegans (spineless and ahr-1) leads to marked increases in basal activity. In mammals, Ahr has numerous ligands, but most are either non-selective (e.g. resveratrol) or highly toxic (e.g., 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)). Thus, we chose to examine a major environmental influence--long term feeding with high fat diet (HFD)--to see if the effects of Ahr are dependent on major metabolic differences. Interestingly, while HFD robustly halved movement across all strains, the QTL position and effects of Ahr remained unchanged, indicating that the effects are independent. The highly consistent effects of Ahr on movement indicate that changes in its constitutive activity have a role on spontaneous movement and may influence human behavior. [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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See detailPharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle.
Pirinen, Eija; Canto, Carles; Jo, Young Suk et al

in Cell metabolism (2014), 19(6), 1034-41

We previously demonstrated that the deletion of the poly(ADP-ribose)polymerase (Parp)-1 gene in mice enhances oxidative metabolism, thereby protecting against diet-induced obesity. However, the ... [more ▼]

We previously demonstrated that the deletion of the poly(ADP-ribose)polymerase (Parp)-1 gene in mice enhances oxidative metabolism, thereby protecting against diet-induced obesity. However, the therapeutic use of PARP inhibitors to enhance mitochondrial function remains to be explored. Here, we show tight negative correlation between Parp-1 expression and energy expenditure in heterogeneous mouse populations, indicating that variations in PARP-1 activity have an impact on metabolic homeostasis. Notably, these genetic correlations can be translated into pharmacological applications. Long-term treatment with PARP inhibitors enhances fitness in mice by increasing the abundance of mitochondrial respiratory complexes and boosting mitochondrial respiratory capacity. Furthermore, PARP inhibitors reverse mitochondrial defects in primary myotubes of obese humans and attenuate genetic defects of mitochondrial metabolism in human fibroblasts and C. elegans. Overall, our work validates in worm, mouse, and human models that PARP inhibition may be used to treat both genetic and acquired muscle dysfunction linked to defective mitochondrial function. [less ▲]

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See detailRegulation of steatohepatitis and PPARgamma signaling by distinct AP-1 dimers.
Hasenfuss, Sebastian C.; Bakiri, Latifa; Thomsen, Martin K. et al

in Cell metabolism (2014), 19(1), 84-95

Nonalcoholic fatty liver disease (NAFLD) affects up to 30% of the adult population in Western societies, yet the underlying molecular pathways remain poorly understood. Here, we identify the dimeric ... [more ▼]

Nonalcoholic fatty liver disease (NAFLD) affects up to 30% of the adult population in Western societies, yet the underlying molecular pathways remain poorly understood. Here, we identify the dimeric Activator Protein 1 as a regulator of NAFLD. Fos-related antigen 1 (Fra-1) and Fos-related antigen 2 (Fra-2) prevent dietary NAFLD by inhibiting prosteatotic PPARgamma signaling. Moreover, established NAFLD and the associated liver damage can be efficiently reversed by hepatocyte-specific Fra-1 expression. In contrast, c-Fos promotes PPARgamma expression, while c-Jun exerts opposing, dimer-dependent functions. Interestingly, JunD was found to be essential for PPARgamma signaling and NAFLD development. This unique antagonistic regulation of PPARgamma by distinct AP-1 dimers occurs at the transcriptional level and establishes AP-1 as a link between obesity, hepatic lipid metabolism, and NAFLD. [less ▲]

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See detailMurine gut microbiota is defined by host genetics and modulates variation of metabolic traits.
McKnite, Autumn M.; Perez-Munoz, Maria Elisa; Lu, Lu et al

in PloS one (2012), 7(6), 39191

The gastrointestinal tract harbors a complex and diverse microbiota that has an important role in host metabolism. Microbial diversity is influenced by a combination of environmental and host genetic ... [more ▼]

The gastrointestinal tract harbors a complex and diverse microbiota that has an important role in host metabolism. Microbial diversity is influenced by a combination of environmental and host genetic factors and is associated with several polygenic diseases. In this study we combined next-generation sequencing, genetic mapping, and a set of physiological traits of the BXD mouse population to explore genetic factors that explain differences in gut microbiota and its impact on metabolic traits. Molecular profiling of the gut microbiota revealed important quantitative differences in microbial composition among BXD strains. These differences in gut microbial composition are influenced by host-genetics, which is complex and involves many loci. Linkage analysis defined Quantitative Trait Loci (QTLs) restricted to a particular taxon, branch or that influenced the variation of taxa across phyla. Gene expression within the gastrointestinal tract and sequence analysis of the parental genomes in the QTL regions uncovered candidate genes with potential to alter gut immunological profiles and impact the balance between gut microbial communities. A QTL region on Chr 4 that overlaps several interferon genes modulates the population of Bacteroides, and potentially Bacteroidetes and Firmicutes-the predominant BXD gut phyla. Irak4, a signaling molecule in the Toll-like receptor pathways is a candidate for the QTL on Chr15 that modulates Rikenellaceae, whereas Tgfb3, a cytokine modulating the barrier function of the intestine and tolerance to commensal bacteria, overlaps a QTL on Chr 12 that influence Prevotellaceae. Relationships between gut microflora, morphological and metabolic traits were uncovered, some potentially a result of common genetic sources of variation. [less ▲]

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See detailSystems genetics of metabolism: the use of the BXD murine reference panel for multiscalar integration of traits.
Andreux, Penelope A.; Williams, Evan UL; Koutnikova, Hana et al

in Cell (2012), 150(6), 1287-99

Metabolic homeostasis is achieved by complex molecular and cellular networks that differ significantly among individuals and are difficult to model with genetically engineered lines of mice optimized to ... [more ▼]

Metabolic homeostasis is achieved by complex molecular and cellular networks that differ significantly among individuals and are difficult to model with genetically engineered lines of mice optimized to study single gene function. Here, we systematically acquired metabolic phenotypes by using the EUMODIC EMPReSS protocols across a large panel of isogenic but diverse strains of mice (BXD type) to study the genetic control of metabolism. We generated and analyzed 140 classical phenotypes and deposited these in an open-access web service for systems genetics (www.genenetwork.org). Heritability, influence of sex, and genetic modifiers of traits were examined singly and jointly by using quantitative-trait locus (QTL) and expression QTL-mapping methods. Traits and networks were linked to loci encompassing both known variants and novel candidate genes, including alkaline phosphatase (ALPL), here linked to hypophosphatasia. The assembled and curated phenotypes provide key resources and exemplars that can be used to dissect complex metabolic traits and disorders. [less ▲]

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See detailNCoR1 is a conserved physiological modulator of muscle mass and oxidative function.
Yamamoto, Hiroyasu; Williams, Evan UL; Mouchiroud, Laurent et al

in Cell (2011), 147(4), 827-39

Transcriptional coregulators control the activity of many transcription factors and are thought to have wide-ranging effects on gene expression patterns. We show here that muscle-specific loss of nuclear ... [more ▼]

Transcriptional coregulators control the activity of many transcription factors and are thought to have wide-ranging effects on gene expression patterns. We show here that muscle-specific loss of nuclear receptor corepressor 1 (NCoR1) in mice leads to enhanced exercise endurance due to an increase of both muscle mass and of mitochondrial number and activity. The activation of selected transcription factors that control muscle function, such as MEF2, PPARbeta/delta, and ERRs, underpins these phenotypic alterations. NCoR1 levels are decreased in conditions that require fat oxidation, resetting transcriptional programs to boost oxidative metabolism. Knockdown of gei-8, the sole C. elegans NCoR homolog, also robustly increased muscle mitochondria and respiration, suggesting conservation of NCoR1 function. Collectively, our data suggest that NCoR1 plays an adaptive role in muscle physiology and that interference with NCoR1 action could be used to improve muscle function. [less ▲]

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