Skeletal muscle Nr4a1 hypomethylation and gene induction reduce insulin sensitivity in sedentary maternal high-fat offspring
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PROVIDER: PRJNA408062 | ENA |
REPOSITORIES: ENA
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Project description:Maternal high-fat consumption has negative effects on the offspring’s obesity/diabetes susceptibility and we hypothesize that epigenetic modifications in the skeletal muscle are partly responsible for this phenotype. To detect genes affected by maternal nutrition, offspring of low-fat (LF) and high-fat (HF) diet fed dams (C57BL/6 mice) received LF diet upon weaning and were sacrificed at an age of 6 or 25 weeks. M. quadriceps gene expression was investigated by microarray analysis revealing upregulation of the nuclear receptor Nr4a1 by maternal HF feeding. This was accompanied by promoter hypomethylation of CpG‑1408 which correlated with higher Nr4a1 gene expression at both ages. Offspring voluntary exercise training normalized Nr4a1 methylation/expression and ameliorated the negative effects of maternal HF feeding on insulin sensitivity. Overall, Nr4a1 expression correlated with higher insulin levels during oral glucose tolerance test and could, therefore, be involved in the programming offspring’s diabetes susceptibility.
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Project description:Nr4a1 deficient rats (Nr4a1-/-) were developed using the fawn hooded hypertensive rat (FHH), which provided a genetic background susceptible to kidney injury. Both groups of animals were evaluated for blood pressure, proteinuria, renal function, and whole transcriptome gene pathway changes. Gene expression profiling was performed at week 8, 16, and 24 using kidney from FHH and Nr4a1-/- rats. To identify differentially expressed gene between FHH and Nr4a1-/- two statistical methods were utilized: (1) FWER (family-wise error rate) procedure, p<0.05 and fold-change M-BM-11.2 or greater; and/or (2) Benjamani and Hochberg FDR (false discovery rate) using p<0.05, and fold-change M-BM-11.2 or greater. Two-way ANOVA using a p<0.01 or lower was performed to identify strain X time interaction effects between groups. Gene networks and functional analysis were evaluated through the use of Ingenuity Pathways Analysis . FHH and Nr4a1-/- rats were grown to 8, 16, and 24 weeks of age and kidney tissue was harvested for transcriptome analysis (n=3 replicates/ per group/ time)
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Project description:We investigate the cellular and molecular mechanisms of tumor suppression by NR4A1 and NR4A3, and show a cell intrinsic essential function in maintenance of hematopoietic stem cell (HSC) homeostasis. In the absence of Nr4a1/3, HSC lost quiescence, became highly proliferative leukemia-stem cell (LSC) that transplanted AML to recipient mice. We further revealed that loss of NR4A1/3 leads to deregulated expression of the key cell cycle regulator Cdkn1c (P57), c-Myc oncogene, and glucose metabolic genes leading to enhanced aerobic glycolysis or Warburg effect in LSCs. Reintroduction of Nr4a1 in LSCs restored HSC quiescence, and reversed Nr4a1/3 deficiency induced P57 suppression and c-Myc overexpression. Collectively, we identify an essential role of Nr4a1/3 in coordinately regulating cell cycle entry and glucose metabolism to prevent uncontrolled stem cell proliferation and AML transformation. These results have major implications for designing therapeutic strategies in AML. To identify NR4A-dependent molecular signaling pathways that may control HSC homeostasis, we performed genome-wide transcript profiling of Lin-Sca1+ (LS) cells from WT and DKO mice. For Affymetrix analysis, we generated three independent pools of RNA from sorted LS cells from 10-20 WT or DKO (2- to 3-week-old) mice per sample.
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Project description:The interaction of genetics and environment play a major role in health and disease. Therefore, modeling experiments to investigate gene-environment interaction in a laboratory setting would provide the opportunity to gain mechanistic insight under controlled conditions. In laboratory research it is unclear if the gene-environment interaction of a sedentary lifestyle predisposes laboratory animals to hypokinetic diseases. Keywords: repeat sample
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Project description:We have revealed that Nr4a family nuclear orphan receptors broadly regulate a transcriptional program in Treg cells. In this study, to give an insight into Nr4a-mediated regulation of the transcriptional program in Treg cells, we performed ChIP-seq experiment using anti-Nr4a1 antibodies and a chromatin lysate from Treg cells. Examination of Nr4a1 binding sites in mouse Treg cells.
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