Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA136439 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Lipid metabolism is recognized as a key process for stem cell maintenance and differentiation but genetic factors that instruct stem cell function by influencing lipid metabolism remain to be delineated. Here we identify Tnfaip2 as an inhibitor of reprogramming of mouse fibroblasts into induced pluripotent stem cells. Tnfaip2 knockout embryonic stem cells (ESCs) exhibit differentiation failure and knockdown of the planarian orthologue, Smed-exoc3, abrogates in vivo differentiation of somatic stem cells, tissue homeostasis, and regeneration. Tnfaip2 deficient ESCs fail to induce synthesis of cellular triacylglycerol (TAG) and lipid droplets (LD) coinciding with reduced expression of Vimentin (Vim) – a known inducer of LD formation. Knockdown of Vim and Tnfaip2 act epistatically in enhancing cellular reprogramming of mouse fibroblasts. Similarly, planarians devoid of Smed-exoc3 displayed acute loss of TAGs. Supplementation of palmitic acid (PA) and palmitoyl-L-carnitine (a mitochondrial carrier of PA) restores the differentiation capacity of Tnfaip2 deficient ESCs as well as stem cell differentiation and organ maintenance in Smed-exoc3-depleted planarians. Together, these results identify a novel pathway, which is essential for stem cell differentiation and organ maintenance by instructing lipid metabolism.
2020-11-16 | GSE148758 | GEO
Project description:Lipid metabolism is recognized as a key process for stem cell maintenance and differentiation but genetic factors that instruct stem cell function by influencing lipid metabolism remain to be delineated. Here we identify Tnfaip2 as an inhibitor of reprogramming of mouse fibroblasts into induced pluripotent stem cells. Tnfaip2 knockout embryonic stem cells (ESCs) exhibit differentiation failure and knockdown of the planarian orthologue, Smed-exoc3, abrogates in vivo differentiation of somatic stem cells, tissue homeostasis, and regeneration. Tnfaip2 deficient ESCs fail to induce synthesis of cellular triacylglycerol (TAG) and lipid droplets (LD) coinciding with reduced expression of Vimentin (Vim) – a known inducer of LD formation. Knockdown of Vim and Tnfaip2 act epistatically in enhancing cellular reprogramming of mouse fibroblasts. Similarly, planarians devoid of Smed-exoc3 displayed acute loss of TAGs. Supplementation of palmitic acid (PA) and palmitoyl-L-carnitine (a mitochondrial carrier of PA) restores the differentiation capacity of Tnfaip2 deficient ESCs as well as stem cell differentiation and organ maintenance in Smed-exoc3-depleted planarians. Together, these results identify a novel pathway, which is essential for stem cell differentiation and organ maintenance by instructing lipid metabolism.
2020-11-16 | GSE134301 | GEO
Project description:The excessive energy is primarily stored as triacylglycerol in lipid droplets in adipocytes, which is hydrolyzed by the actions of lipases upon energy demand. In this study, the potential role of PAK4 in the lipolysis process in adipocytes was investigated. To elucidate functional outcomes, we performed RNA-sequencing analysis using littermate WT and adipose tissue-specific Pak4 KO mice in fasted conditions.
2023-10-15 | GSE214769 | GEO
Project description:In zebrafish, maternally deposited yolk is the source of nutrients for embryogenesis prior to digestive system maturation. Yolk nutrients are processed and secreted to the growing organism by an extra-embryonic tissue, the yolk syncytial layer (YSL). Export of lipid from the YSL occurs through the production of triacylglycerol-rich lipoproteins. Here we report that mutations in the triacylglycerol synthesis enzyme, diacylglycerol acyltransferase-2 (Dgat2), cause yolk sac opacity due to aberrant accumulation of cytoplasmic lipid droplets in the YSL. Though triacylglycerol synthesis continues, it is not properly coupled to lipoprotein production as dgat2 mutants produce fewer, smaller, ApoB-containing lipoproteins. Unlike DGAT2-null mice, which are lipopenic and die soon after birth, zebrafish dgat2 mutants are viable, fertile and exhibit normal mass and adiposity. Residual Dgat activity cannot be explained by the activity of other known Dgat isoenzymes, as dgat1a;dgat1b;dgat2 triple mutants continue to produce YSL lipid droplets and remain viable as adults. Further, the newly identified diacylglycerol acyltransferase, Tmem68, is also not responsible for the residual triacylglycerol synthesis activity. Unlike overexpression of Dgat1a and Dgat1b, monoacylglycerol acyltransferase-3 (Mogat3b) overexpression does not rescue yolk opacity, suggesting it does not possess Dgat activity in the YSL. However, mogat3b;dgat2 double mutants exhibit increased yolk opacity and often have structural alterations of the yolk extension. Quadruple mogat3b;dgat1a;dgat1b;dgat2 mutants either have severely reduced viability and stunted growth, or do not survive past 3 days post fertilization, depending on the dgat2 mutant allele present. Our study highlights the remarkable ability of vertebrates to synthesize triacylglycerol through multiple biosynthetic pathways.
2024-11-07 | GSE279170 | GEO
Project description:Introgressed variants from other species can be an important source of genetic variation because they may arise rapidly, can include multiple mutations on a single haplotype, and have often been pretested by selection in the species of origin. Although introgressed alleles are generally deleterious, several studies have reported introgression as the source of adaptive alleles-including the rodenticide-resistant variant of Vkorc1 that introgressed from Mus spretus into European populations of Mus musculus domesticus. Here, we conducted bidirectional genome scans to characterize introgressed regions into one wild population of M. spretus from Spain and three wild populations of M. m. domesticus from France, Germany, and Iran. Despite the fact that these species show considerable intrinsic postzygotic reproductive isolation, introgression was observed in all individuals, including in the M. musculus reference genome (GRCm38). Mus spretus individuals had a greater proportion of introgression compared with M. m. domesticus, and within M. m. domesticus, the proportion of introgression decreased with geographic distance from the area of sympatry. Introgression was observed on all autosomes for both species, but not on the X-chromosome in M. m. domesticus, consistent with known X-linked hybrid sterility and inviability genes that have been mapped to the M. spretus X-chromosome. Tract lengths were generally short with a few outliers of up to 2.7 Mb. Interestingly, the longest introgressed tracts were in olfactory receptor regions, and introgressed tracts were significantly enriched for olfactory receptor genes in both species, suggesting that introgression may be a source of functional novelty even between species with high barriers to gene flow.
| S-EPMC8784167 | biostudies-literature
Project description:The ability of Mycobacterium tuberculosis (Mtb) to establish latency directly impacts disease and response to treatment but the host’s influence on this switch remains elusive. Using a novel Mtb reporter strain to separate macrophages infected with replicating or latent Mtb, we performed transcriptomics and genome-wide CRISPR screens. After validating the recovery of known susceptibility loci from TB GWAS as modifiers of active replication, we identified multiple pathways and novel modulators of latency. We validated multiple controllers of latency and mechanistically characterized the transporter MMGT1. MMGT1-deficient macrophages upregulated lipid metabolism genes and accumulated lipid droplets during infection. Critically, targeting triacylglycerol synthesis reduced both droplet formation and Mtb latency. We identified GPR156, an orphan GPCR as a key inducer of droplet accumulation in ΔMMGT1 cells. Altogether, our work uncovers the role of MMGT1-GPR156-lipid droplets in the induction of Mtb latency, suggesting that host-directed therapies could be used to modulate Mtb phenotypes during infection.
2023-06-01 | GSE210690 | GEO
Project description:The ability of Mycobacterium tuberculosis (Mtb) to establish latency directly impacts disease and response to treatment but the host’s influence on this switch remains elusive. Using a novel Mtb reporter strain to separate macrophages infected with replicating or latent Mtb, we performed transcriptomics and genome-wide CRISPR screens. After validating the recovery of known susceptibility loci from TB GWAS as modifiers of active replication, we identified multiple pathways and novel modulators of latency. We validated multiple controllers of latency and mechanistically characterized the transporter MMGT1. MMGT1-deficient macrophages upregulated lipid metabolism genes and accumulated lipid droplets during infection. Critically, targeting triacylglycerol synthesis reduced both droplet formation and Mtb latency. We identified GPR156, an orphan GPCR as a key inducer of droplet accumulation in ΔMMGT1 cells. Altogether, our work uncovers the role of MMGT1-GPR156-lipid droplets in the induction of Mtb latency, suggesting that host-directed therapies could be used to modulate Mtb phenotypes during infection.
2023-06-01 | GSE210689 | GEO
Project description:The ability of Mycobacterium tuberculosis (Mtb) to establish latency directly impacts disease and response to treatment but the host’s influence on this switch remains elusive. Using a novel Mtb reporter strain to separate macrophages infected with replicating or latent Mtb, we performed transcriptomics and genome-wide CRISPR screens. After validating the recovery of known susceptibility loci from TB GWAS as modifiers of active replication, we identified multiple pathways and novel modulators of latency. We validated multiple controllers of latency and mechanistically characterized the transporter MMGT1. MMGT1-deficient macrophages upregulated lipid metabolism genes and accumulated lipid droplets during infection. Critically, targeting triacylglycerol synthesis reduced both droplet formation and Mtb latency. We identified GPR156, an orphan GPCR as a key inducer of droplet accumulation in ΔMMGT1 cells. Altogether, our work uncovers the role of MMGT1-GPR156-lipid droplets in the induction of Mtb latency, suggesting that host-directed therapies could be used to modulate Mtb phenotypes during infection.
2023-06-01 | GSE210687 | GEO
Project description:Translational research is commonly performed in the C57B6/J mouse strain, chosen for its genetic homogeneity and phenotypic uniformity. Here, we evaluate the suitability of the white-footed deer mouse (Peromyscus leucopus) as a model organism for aging research, offering a comparative analysis against C57B6/J and diversity outbred (DO) Mus musculus strains. Our study includes comparisons of body composition, skeletal muscle function, and cardiovascular parameters, shedding light on potential applications and limitations of P. leucopus in aging studies. Notably, P. leucopus exhibits distinct body composition characteristics, emphasizing reduced muscle force exertion and a unique metabolism, particularly in fat mass. Cardiovascular assessments showed changes in arterial stiffness, challenging conventional assumptions and highlighting the need for a nuanced interpretation of aging-related phenotypes. Our study also highlights inherent challenges associated with maintaining and phenotyping P. leucopus cohorts. Behavioral considerations, including anxiety-induced responses during handling and phenotyping assessment, pose obstacles in acquiring meaningful data. Moreover, the unique anatomy of P. leucopus necessitates careful adaptation of protocols designed for Mus musculus. While showcasing potential benefits, further extensive analyses across broader age ranges and larger cohorts are necessary to establish the reliability of P. leucopus as a robust and translatable model for aging studies.
| S-EPMC11335981 | biostudies-literature
Project description:Non-alcoholic fatty liver disease (NAFLD) is a major public health burden and it covers a spectrum of diseases. NAFLD starts with the accumulation of lipid droplets (LDs) within hepatocytes (steatosis). Part of the challenge of studying the mechanistic processes involved in LD accumulation and their implications on the pathogenesis of human NAFLD is due to the available models. Investigating hepatic LDs in humans is challenging and relies on liver biopsies, meaning only cross-sectional data be obtained. On the other hand, LD patterns in in vitro models are poorly defined and rarely reported. Diacylgylcerol acyltransferase (DGAT)2 is one of two enzymes that carry out the final committed step in triacylglycerol (TAG) synthesis. It is unclear whether the enzymes are able to compensate for each other or whether they have distinct roles. It has been hypothesised that DGAT1 primarily utilises exogenous fatty acids and DGAT2 uses de novo-derived fatty acids. Given the important role of this enzyme in TAG synthesis and accumulation, the aims of this study are first to create a cellular model of intrahepatocellular TAG accumulation by manipulating nutritional substrates and to investigate intracellular metabolism in wildtype and DGAT2 knockout cells under these conditions. The experimental workflow for this study is as follows: Huh7 cells (either wild type or knockout) were grown in media containing 11 mM glucose and 2% human serum (HS) for seven days before additional sugars and fatty acids (FAs) were added for a further seven days. All treatments contained 11 mM glucose and 2% HS, either with 200 µM FAs (low fat low sugar; LFLS), 5.5 mM fructose + 200 µM FAs (low fat high sugar; LFHS) or 5.5 mM fructose + 800 µM FAs (high fat high sugar; HFHS). FA metabolism, lipid droplet characteristics and transcriptomic signatures were investigated.
2020-08-21 | E-MTAB-7884 | biostudies-arrayexpress