Knocking down CDKN2A in 3D hiPSC-derived brown adipose progenitors potentiates differentiation, oxydative metabolism and browning process
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ABSTRACT:
PROVIDER: PRJNA925454 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23118726_1.fastq.gz | Fastqsanger.gz | |||
| SRR23118726_2.fastq.gz | Fastqsanger.gz | |||
| SRR23118727_1.fastq.gz | Fastqsanger.gz | |||
| SRR23118727_2.fastq.gz | Fastqsanger.gz | |||
| SRR23118728_1.fastq.gz | Fastqsanger.gz |
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Project description:Human induced pluripotent stem cells (hiPSCs) have the potential to be differentiated into any cell type, making these cells a relevant tool for therapeutic purposes such as cell-based therapies. In particular, they show great promise for obesity treatment as they represent an unlimited source of brown/brite adipose progenitors (hiPSC-BAPs), although the low brown/brite adipocyte differen-tiation potential in 2D culture represents a strong limitation for clinical use. In adipose tissue, be-sides to its cell cycle regulator functions, the cyclin-dependent kinase inhibitor 2A (CDKN2A) lo-cus modulates the commitment of stem cells to the brown-like type fate, mature adipocyte energy metabolism and browning of adipose tissue. Here, using a new method of hiPSC-BAPs 3D culture, via the formation of an organoid-like structure, we silenced CDKN2A expression during hiPSC-BAP adipogenic differentiation and observed that knocking down CDKN2A potentiates adipogenesis, oxidative metabolism and browning process, resulting in brown-like adipocytes by promoting UCP1 expression and beiging markers. Our results suggest that modulating CDKN2A levels could be relevant for hiPSC-BAPs cell-based therapies.
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Project description:Epithelioid hemangioendothelioma (EHE) is a rare vascular sarcoma that is associated with a TAZ-CAMTA1 fusion in greater than 90% of cases and loss of CDKN2A in human EHE tumors is associated with late stage disease. Murine EHE tumors were created by conditionally expressing TAZ-CAMTA1 and conditionally knocking out Cdkn2a within vascular endothelium. Resultant tumors were used for single cell RNA sequencing and compared against age matched wild type mice tissue.
2022-12-16 | GSE220540 | GEO
Project description:Enzymatic browning on the cut edge of lettuce significantly limits its quality and shelf life. To characterize its molecular mechanisms, we performed comparative transcriptome analysis of three Romaine lettuce cultivars, Parris Island Cos (PC) with low browning potential, Tall Guzmaine (TG) with high degree of browning and Clemente (CL), a medium degree of browning cultivar derived from TG x PC. Before cutting, the phenylpropanoid and oxidative stress genes, such as PAL1, MYB1 and PPO were up-regulated in PC as compared to TG, while the expressions of genes involved in auxin, cytokinin hormone signalings and defense, such as ARF, AHP and PTI in PC were higher than TG. The transcript levels of all these genes in CL were somewhere between TG and PC. On day 3 after cutting when browning was shown up in TG, the expression of these phenylpropanoid and oxidative stress genes were remarkably increased in all three cultivars, even though their levels in TG were still higher than those in PC and CI. In comparison, expressions of the hormone and defense genes were reduced in all three cultivars, but their levels in PC were higher than CI and TG. Exogenous application of IAA and 6-BA inhibited lettuce browning possibly by alleviating the burst of those browning related genes, such as PAL1 and PPO1. These results demonstrate that lettuce tissue browning is controlled by reduced growth hormone (mainly auxin) level and increased phenolics biosynthesis and oxidation. This study provides the useful knowledge and functional markers for lettuce breeders and industry to select low tissue browning cultivar and manage lettuce quality during storage and processing.
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Project description:OBJECTIVES:Genome-wide association studies have reported that DNA polymorphisms at the CDKN2A locus modulate fasting glucose in human and contribute to type 2 diabetes (T2D) risk. Yet the causal relationship between this gene and defective energy homeostasis remains elusive. Here we sought to understand the contribution of Cdkn2a to metabolic homeostasis. METHODS:We first analyzed glucose and energy homeostasis from Cdkn2a-deficient mice subjected to normal or high fat diets. Subsequently Cdkn2a-deficient primary adipose cells and human-induced pluripotent stem differentiated into adipocytes were further characterized for their capacity to promote browning of adipose tissue. Finally CDKN2A levels were studied in adipocytes from lean and obese patients. RESULTS:We report that Cdkn2a deficiency protects mice against high fat diet-induced obesity, increases energy expenditure and modulates adaptive thermogenesis, in addition to improving insulin sensitivity. Disruption of Cdkn2a associates with increased expression of brown-like/beige fat markers in inguinal adipose tissue and enhances respiration in primary adipose cells. Kinase activity profiling and RNA-sequencing analysis of primary adipose cells further demonstrate that Cdkn2a modulates gene networks involved in energy production and lipid metabolism, through the activation of the Protein Kinase A (PKA), PKG, PPARGC1A and PRDM16 signaling pathways, key regulators of adipocyte beiging. Importantly, CDKN2A expression is increased in adipocytes from obese compared to lean subjects. Moreover silencing CDKN2A expression during human-induced pluripotent stem cells adipogenic differentiation promoted UCP1 expression. CONCLUSION:Our results offer novel insight into brown/beige adipocyte functions, which has recently emerged as an attractive therapeutic strategy for obesity and T2D. Modulating Cdkn2a-regulated signaling cascades may be of interest for the treatment of metabolic disorders.
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Project description:Common genetic variants in a 58-kilobase (kb) region of chromosome 9p21, near the CDKN2A/B cell proliferation inhibitor genes, are strongly associated with coronary artery disease (CAD). We previously reported a congenic mouse model harboring an atherosclerosis susceptibility locus in a region of homology with the human 9p21 locus. We now report markedly decreased Cdkn2a (cyclin-dependent kinase inhibitor 2a) mRNA expression in macrophages and increased circulating levels of Ly6Chigh inflammatory monocytes in congenic mice compared to controls. A bone marrow (BM) transplantation study revealed that BM-derived cells from Cdkn2a+/- mice are capable of conferring accelerated atherosclerosis, increased inflammatory monocyte subsets and monocyte proliferation in the Ldlr-/- mouse model. These findings provide a mechanistic link between decreased expression of Cdkn2a transcripts, increased monocyte proliferation, and accelerated atherosclerosis. Aorta and macrophages from ten C57BL/6.MOLFc4(51Mb)-Ldlr-/- mice and their control C57BL/6-Ldlr-/- were obtained, RNA purified and hybridized to GPL9734 Affimetrix microarrays.
2011-09-30 | E-GEOD-24342 | biostudies-arrayexpress
Project description:Common genetic variants in a 58-kilobase (kb) region of chromosome 9p21, near the CDKN2A/B cell proliferation inhibitor genes, are strongly associated with coronary artery disease (CAD). We previously reported a congenic mouse model harboring an atherosclerosis susceptibility locus in a region of homology with the human 9p21 locus. We now report markedly decreased Cdkn2a (cyclin-dependent kinase inhibitor 2a) mRNA expression in macrophages and increased circulating levels of Ly6Chigh inflammatory monocytes in congenic mice compared to controls. A bone marrow (BM) transplantation study revealed that BM-derived cells from Cdkn2a+/- mice are capable of conferring accelerated atherosclerosis, increased inflammatory monocyte subsets and monocyte proliferation in the Ldlr-/- mouse model. These findings provide a mechanistic link between decreased expression of Cdkn2a transcripts, increased monocyte proliferation, and accelerated atherosclerosis.
2011-10-01 | GSE24342 | GEO
Project description:As obesity has becoming an urged issue nowadays, delineation of the mechanisms of WAT tissue white-browning and beige adipose origin are of important topic. By the use of snRNA-seq, we can outline LepR cells play important role in the white-browning process and investigate the mechanisms participate at different white-browning treatments.
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