Mouse Phenome Database

Grubb, Stephen C.; Maddatu, Terry P.; Bult, Carol J.; Bogue, Molly A.

doi:10.1093/nar/gkn778

Cited by 93 publications

(73 citation statements)

References 16 publications

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“…These mice are genetically highly divergent from the standard laboratory strains, thereby more accurately modeling the greater evolutionarily-selected genetic diversity seen in human populations 9, 10 . Additionally, consomic strains of C57BL/6J (B6) mice carrying chromosomes from PWD (B6.Chr PWD ) have been established 11 , and have been useful in mapping QTL controlling various complex phenotypes 12, 13 . We have recently utilized this approach to begin to map QTL controlling susceptibility to experimental autoimmune encephalomyelitis (EAE), the principal autoimmune animal model of MS 14 .…”

Section: Introductionmentioning

confidence: 99%

Natural genetic variation profoundly regulates gene expression in immune cells and dictates susceptibility to CNS autoimmunity

et al. 2016

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Regulation of gene expression in immune cells is known to be under genetic control, and likely contributes to susceptibility to autoimmune diseases, such as multiple sclerosis (MS). How this occurs in concert across multiple immune cell types is poorly understood. Using a mouse model that harnesses the genetic diversity of wild-derived mice, more accurately reflecting genetically diverse human populations, we provide an extensive characterization of the genetic regulation of gene expression in five different naïve immune cell types relevant to MS. The immune cell transcriptome is shown to be under profound genetic control, exhibiting diverse patterns: global, cell-specific, and sex-specific. Bioinformatic analysis of the genetically-controlled transcript networks reveals reduced cell type-specificity and inflammatory activity in wild-derived PWD/PhJ mice, compared with the conventional laboratory strain C57BL/6J. Additionally, candidate MS-GWAS genes were significantly enriched among transcripts overrepresented in C57BL/6J cells compared to PWD. These expression level differences correlate with robust differences in susceptibility to experimental autoimmune encephalomyelitis, the principal model of MS, and skewing of the encephalitogenic T cell responses. Taken together, our results provide functional insights into the genetic regulation of the immune transcriptome, and shed light on how this in turn contributes to susceptibility to autoimmune disease.

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Section: Introductionmentioning

confidence: 99%

Natural genetic variation profoundly regulates gene expression in immune cells and dictates susceptibility to CNS autoimmunity

et al. 2016

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“…1b). Adipose Nnmt expression correlates highly with per cent fat mass in diet-induced obesity across 20 different mouse strains 18 , and with expression of retinol-binding protein 4 ( Rbp4 ) ( r =0.90, P <0.0001 by Pearson correlation coefficient, two-tailed test), an adipokine that contributes to insulin resistance 2 (Supplementary Fig. 2a, b).…”

mentioning

confidence: 99%

Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity

Kraus

Yang

Kong

et al. 2014

Nature

410

488

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In obesity and type 2 diabetes, Glut4 glucose transporter expression is decreased selectively in adipocytes1. Adipose-specific knockout or overexpression of Glut4 alters systemic insulin sensitivity2. Here we show, using DNA array analyses, that nicotinamide N-methyltransferase (Nnmt) is the most strongly reciprocally regulated gene when comparing gene expression in white adipose tissue (WAT) from adipose-specific Glut4-knockout or adipose-specific Glut4-overexpressing mice with their respective controls. NNMT methylates nicotinamide (vitamin B3) using S-adenosylmethionine (SAM) as a methyl donor3,4. Nicotinamide is a precursor of NAD+, an important cofactor linking cellular redox states with energy metabolism5. SAM provides propylamine for polyamine biosynthesis and donates a methyl group for histone methylation6. Polyamine flux including synthesis, catabolism and excretion, is controlled by the rate-limiting enzymes ornithine decarboxylase (ODC) and spermidine–spermine N1-acetyltransferase (SSAT; encoded by Sat1) and by polyamine oxidase (PAO), and has a major role in energy metabolism7,8. We report that NNMT expression is increased in WAT and liver of obese and diabetic mice. Nnmt knockdown in WAT and liver protects against diet-induced obesity by augmenting cellular energy expenditure. NNMT inhibition increases adipose SAM and NAD+ levels and upregulates ODC and SSAT activity as well as expression, owing to the effects of NNMT on histone H3 lysine 4 methylation in adipose tissue. Direct evidence for increased polyamine flux resulting from NNMT inhibition includes elevated urinary excretion and adipocyte secretion of diacetylspermine, a product of polyamine metabolism. NNMT inhibition in adipocytes increases oxygen consumption in an ODC-, SSAT- and PAO-dependent manner. Thus, NNMT is a novel regulator of histone methylation, polyamine flux and NAD+-dependent SIRT1 signalling, and is a unique and attractive target for treating obesity and type 2 diabetes.

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“…Unique wild-derived behavioral traits including very high locomotor activity are also characteristic of MSM [21,33,56,57]. additionally, this strain was selected as one of the target strains in the Mouse Phenome Project of the Jackson Laboratory, and the accumulated phenotypic data are now available online [16,39]. The MSM strain likely bears additional intriguing phenotypes that are specific to M. m. molossinus and not found in other mouse subspecies.…”

Section: Japanese Wild-mouse-derived Inbred Strain For Studies Of Quamentioning

confidence: 99%

Complex Quantitative Traits Cracked by the Mouse Inter-Subspecific Consomic Strains

Takada

Shiroishi

2012

Exp. Anim.

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Mammalian quantitative traits that are observed at the whole-body level, such as body weight and length and blood biochemical parameters, are determined by the cooperative effects of multiple genetic and epigenetic factors as well as environmental factors. This complexity has hampered the genetic analysis of quantitative traits. To overcome this difficulty, we have established a full set of consomic mouse strains, also known as chromosome substitution strains, by replacing every chromosome of the classical inbred strain C57BL/6J with its counterpart from the Japanese wildmouse-derived inbred strain MSM/Ms. The core components of the genomes of these two strains originated from different mouse subspecies. The inter-subspecific large-genome divergence and phenotypic differences between the two strains allowed the identification of genetic determinants for many quantitative traits by comprehensive phenotype screening. For some quantitative traits, the genetic determinants could be dissected into multiple chromosomes, thereby reflecting strain differences between C57BL/6J and MSM/Ms and their simple additive effects on the background of the consomic host strain. For other quantitative traits, the measured values of some consomic strains often far exceeded the range of the two parental strains, which suggests that nonadditive genetic interactions occur among multiple genes located on the substituted MSM/Ms chromosomes and the consomic host chromosomes. Thus, the inter-subspecific consomic strains are unique tools that can be used to identify both additive and nonadditive genetic effects on quantitative complex traits.

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Mouse Phenome Database

Cited by 93 publications

References 16 publications

Natural genetic variation profoundly regulates gene expression in immune cells and dictates susceptibility to CNS autoimmunity

Natural genetic variation profoundly regulates gene expression in immune cells and dictates susceptibility to CNS autoimmunity

Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity

Complex Quantitative Traits Cracked by the Mouse Inter-Subspecific Consomic Strains

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