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See detailA Dietary Fiber-Deprived Gut Microbiota Degrades the Colonic Mucus Barrier and Enhances Pathogen Susceptibility.
Desai, Mahesh S.; Seekatz, Anna M.; Koropatkin, Nicole M. et al

in Cell (2016), 167(5), 1339-135321

Despite the accepted health benefits of consuming dietary fiber, little is known about the mechanisms by which fiber deprivation impacts the gut microbiota and alters disease risk. Using a gnotobiotic ... [more ▼]

Despite the accepted health benefits of consuming dietary fiber, little is known about the mechanisms by which fiber deprivation impacts the gut microbiota and alters disease risk. Using a gnotobiotic mouse model, in which animals were colonized with a synthetic human gut microbiota composed of fully sequenced commensal bacteria, we elucidated the functional interactions between dietary fiber, the gut microbiota, and the colonic mucus barrier, which serves as a primary defense against enteric pathogens. We show that during chronic or intermittent dietary fiber deficiency, the gut microbiota resorts to host-secreted mucus glycoproteins as a nutrient source, leading to erosion of the colonic mucus barrier. Dietary fiber deprivation, together with a fiber-deprived, mucus-eroding microbiota, promotes greater epithelial access and lethal colitis by the mucosal pathogen, Citrobacter rodentium. Our work reveals intricate pathways linking diet, the gut microbiome, and intestinal barrier dysfunction, which could be exploited to improve health using dietary therapeutics. [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 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 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 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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See detailThe TRIM-NHL protein TRIM32 activates microRNAs and prevents self-renewal in mouse neural progenitors.
Schwamborn, Jens Christian UL; Berezikov, Eugene; Knoblich, Juergen A.

in Cell (2009), 136(5), 913-25

In the mouse neocortex, neural progenitor cells generate both differentiating neurons and daughter cells that maintain progenitor fate. Here, we show that the TRIM-NHL protein TRIM32 regulates protein ... [more ▼]

In the mouse neocortex, neural progenitor cells generate both differentiating neurons and daughter cells that maintain progenitor fate. Here, we show that the TRIM-NHL protein TRIM32 regulates protein degradation and microRNA activity to control the balance between those two daughter cell types. In both horizontally and vertically dividing progenitors, TRIM32 becomes polarized in mitosis and is concentrated in one of the two daughter cells. TRIM32 overexpression induces neuronal differentiation while inhibition of TRIM32 causes both daughter cells to retain progenitor cell fate. TRIM32 ubiquitinates and degrades the transcription factor c-Myc but also binds Argonaute-1 and thereby increases the activity of specific microRNAs. We show that Let-7 is one of the TRIM32 targets and is required and sufficient for neuronal differentiation. TRIM32 is the mouse ortholog of Drosophila Brat and Mei-P26 and might be part of a protein family that regulates the balance between differentiation and proliferation in stem cell lineages. [less ▲]

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See detailAntagonistic interactions between FGF and BMP signaling pathways: a mechanism for positioning the sites of tooth formation.
Neubuser, A.; Peters, H.; Balling, Rudi UL et al

in Cell (1997), 90(2), 247-55

Vertebrate organogenesis is initiated at sites that are often morphologically indistinguishable from the surrounding region. Here we have identified Pax9 as a marker for prospective tooth mesenchyme prior ... [more ▼]

Vertebrate organogenesis is initiated at sites that are often morphologically indistinguishable from the surrounding region. Here we have identified Pax9 as a marker for prospective tooth mesenchyme prior to the first morphological manifestation of odontogenesis. We provide evidence that the sites of Pax9 expression in the mandibular arch are positioned by the combined activity of two signals, one (FGF8) that induces Pax9 expression and the other (BMP2 and BMP4) that prevents this induction. Thus it appears that the position of the teeth is determined by a combination of two different types of signaling molecules produced in wide but overlapping domains rather than by a single localized inducer. We suggest that a similar mechanism may be used for specifying the sites of development of other organs. [less ▲]

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See detailAn actin-binding site containing a conserved motif of charged amino acid residues is essential for the morphogenic effect of villin.
Friederich, Evelyne UL; Vancompernolle, K.; Huet, C. et al

in Cell (1992), 70(1), 81-92

The actin-binding protein villin induces microvillus growth and reorganization of the cytoskeleton in cells that do not normally produce this protein. Transfection of mutagenized villin cDNAs into CV-1 ... [more ▼]

The actin-binding protein villin induces microvillus growth and reorganization of the cytoskeleton in cells that do not normally produce this protein. Transfection of mutagenized villin cDNAs into CV-1 cells was used to show that a conserved, COOH-terminally located cluster of charged amino acid residues (KKEK) is crucial for the morphogenic activity of villin in vivo. In vitro experiments with a 22 amino acid synthetic peptide corresponding to this region of villin provide evidence that this motif is part of an F-actin-binding site that induces G-actin to polymerize. Chemical cross-linking of actin to this peptide, the effects of amino acid substitutions in peptides, and the behavior of villin variants further corroborate the participation of the KKEK sequence in actin contacts. [less ▲]

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See detailVariations of cervical vertebrae after expression of a Hox-1.1 transgene in mice.
Kessel, M.; Balling, Rudi UL; Gruss, P.

in Cell (1990), 61(2), 301-8

To understand the function of murine homeobox genes, a genetic analysis is mandatory. We generated gain-of-function mutants by introducing genomic sequences of the Hox-1.1 gene under the control of a ... [more ▼]

To understand the function of murine homeobox genes, a genetic analysis is mandatory. We generated gain-of-function mutants by introducing genomic sequences of the Hox-1.1 gene under the control of a chicken beta-actin promoter into mice. Our previous data had shown that these transgenic mice are nonviable after birth and are born with craniofacial abnormalities. In a subsequent detailed analysis of severely affected animals, malformations of the basioccipital bone, the atlas, and the axis were observed. Manifestation of an additional vertebra, a proatlas, occurred at the craniocervical transition. The dominant interference of the Hox-1.1 transgene with developmental programs seems to occur around day 9 of gestation, the time of neural crest migration and somite differentiation. We discuss the resulting phenotype with respect to a developmental control function of Hox-1.1. [less ▲]

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See detailVillin induces microvilli growth and actin redistribution in transfected fibroblasts.
Friederich, Evelyne UL; Huet, C.; Arpin, M. et al

in Cell (1989), 59(3), 461-75

The function of villin, an actin-binding protein, has been investigated by transfecting fibroblasts with cloned human cDNAs encoding wild-type villin or functional villin domains. Synthesis of large ... [more ▼]

The function of villin, an actin-binding protein, has been investigated by transfecting fibroblasts with cloned human cDNAs encoding wild-type villin or functional villin domains. Synthesis of large amounts of villin induced the growth of numerous long microvilli on cell surfaces together with the redistribution of F-actin. These microvilli contained a cytoskeleton of F-actin, and their appearance was frequently accompanied by the disappearance of stress fibers. The complete villin gene sequence was required to exert its morphogenic effect. Villin lacking one actin-binding domain (113 amino acids), located at its carboxyterminal end, did not induce growth if microvilli or stress fiber disruption. Our results indicate that villin plays a key role in vivo in the morphogenesis of microvilli. [less ▲]

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See detailCraniofacial abnormalities induced by ectopic expression of the homeobox gene Hox-1.1 in transgenic mice.
Balling, Rudi UL; Mutter, G.; Gruss, P. et al

in Cell (1989), 58(2), 337-47

Hox-1.1 is a murine homeobox-containing gene expressed in a time- and cell-specific manner during embryogenesis. We have generated transgenic mice that ectopically express Hox-1.1 from the chicken beta ... [more ▼]

Hox-1.1 is a murine homeobox-containing gene expressed in a time- and cell-specific manner during embryogenesis. We have generated transgenic mice that ectopically express Hox-1.1 from the chicken beta-actin promoter. In these mice Hox-1.1 expression was changed to an almost ubiquitous pattern. Ectopic expression of Hox-1.1 leads to death of the transgenic animals shortly after birth and is associated with multiple craniofacial anomalies, such as cleft palate, open eyes at birth, and nonfused pinnae. This phenotype is similar to the effects seen after systemic administration of retinoic acid during gestation. This suggests that retinoic acid embryopathy and the specific developmental defects caused by ectopic expression of a potential developmental control gene share a common pathogenic mechanism. [less ▲]

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See detailundulated, a mutation affecting the development of the mouse skeleton, has a point mutation in the paired box of Pax 1.
Balling, Rudi UL; Deutsch, U.; Gruss, P.

in Cell (1988), 55(3), 531-5

undulated (un) homozygous mice exhibit vertebral malformations along the entire rostro-caudal axis. Pax 1, a murine paired box-containing gene, is expressed in ventral sclerotome cells and later in ... [more ▼]

undulated (un) homozygous mice exhibit vertebral malformations along the entire rostro-caudal axis. Pax 1, a murine paired box-containing gene, is expressed in ventral sclerotome cells and later in intervertebral disks along the entire vertebral column. We localized the Pax 1 gene on chromosome 2 between beta 2-microglobulin and the agouti locus to an area where un maps. DNA analysis of the un mutant revealed a point mutation in a highly conserved part of the paired box of Pax 1, leading to a Gly-Ser replacement. The chromosomal location and the mutation in the paired box of un mice in conjunction with Pax 1 gene expression in wild-type mice implicate a causative role of Pax 1 in generation of the vertebral column. [less ▲]

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