Gene expression in anergic and naïve CD4 T cells deficient for Nr4a1 and Nr4a3
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA740332 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14892315_1.fastq.gz | Fastqsanger.gz | |||
| SRR14892315_2.fastq.gz | Fastqsanger.gz | |||
| SRR14892316_1.fastq.gz | Fastqsanger.gz | |||
| SRR14892316_2.fastq.gz | Fastqsanger.gz | |||
| SRR14892317_1.fastq.gz | Fastqsanger.gz |
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Project description:The NR4A family of nuclear receptors are upregulated by acute and chronic antigen stimulation, and play redundant, tolerogenic roles in T and B cells. To bypass their obligate function in the Treg lineage, we generated competitive chimeras with Nr4a1-/-Nr4a3-/- (double knockout or DKO) bone marrow mixed with congenically marked WT bone marrow at a 1:5 ratio. As a result of a defect in Treg production by DKO cells, Treg in mixed chimeras are almost exclusively of WT origin. By contrast, we generate an approximately 1:1 DKO:WT ratio in the peripheral T cell compartment because DKO cells escape negative selection. After reconstitution, we observed pronounced accumulation of anergic DKO CD4 T cells, but a defect in functional tolerance resulting in autoantibody production. Based on these studies and published literature, we hypothesize that the NR4A family regulate TCR-induced transcripts in both naive and anergic CD4 T cells. To identify such targets, we sorted naive and anergic CD4 T cells of either WT or DKO genotype (CD45.1+ or CD45.1-) on the basis of CD73/FR4/CD44 expression from these chimeras directly into RLT buffer. In parallel, we stimulated sorted naive CD4 T cells of each genotype in vitro with plate-bound anti-CD3 and anti-CD28 stimulation for 3 hrs and then generated RLT lysates. We made biological triplicate samples of each condition (naive WT and DKO, naive stimulated WT and DKO, anergic WT and DKO) resulting in 6 different populations x 3 replicates = 18 samples. Samples were subjected to library prep and bulk RNA sequencing to identify DEG.
2021-06-24 | GSE178782 | GEO
Project description:Loss of functional beta-cell mass is a hallmark of Type 1 and Type 2 diabetes, and methods for restoring these cells are needed. Nkx6.1 induces beta-cell proliferation, but the pathway by which Nkx6.1 activates beta-cell expansion has not been defined. Here we demonstrate that Nkx6.1 induces expression of the Nr4a1 and Nr4a3 orphan nuclear receptors, and that these factors are both necessary and sufficient for Nkx6.1-mediated β-cell proliferation. Overexpression of the Nr4a receptors results in increased expression of key cell cycle inducers E2F1 and cyclin E1. Furthermore, Nr4a receptors induce components of the anaphase-promoting complex, including Ube2c. We set up a microarray using primary rat islets that were left untreated or transduced with adenoviruses overexpressing GFP, Nr4a1 or Nr4a3 for 48 h.
2014-02-18 | E-GEOD-55078 | biostudies-arrayexpress
Project description:Loss of functional beta-cell mass is a hallmark of Type 1 and Type 2 diabetes, and methods for restoring these cells are needed. We have previously reported that overexpression of the homeodomain transcription factor Nkx6.1 in rat pancreatic islets induces beta-cell proliferation and enhances glucose-stimulated insulin secretion, but the pathway by which Nkx6.1 activates beta-cell expansion has not been defined. Here we demonstrate that Nkx6.1 induces expression of the Nr4a1 and Nr4a3 orphan nuclear receptors, and that these factors are both necessary and sufficient for Nkx6.1-mediated beta-cell proliferation. Consistent with this finding, global knockout of Nr4a1 results in a decrease in beta-cell area in neonatal and young mice. Overexpression of Nkx6.1 and the Nr4a receptors results in increased expression of key cell cycle inducers E2F1 and cyclin E1. Furthermore, Nkx6.1 and Nr4a receptors induce components of the anaphase-promoting complex, including Ube2c, resulting in degradation of the cell cycle inhibitor p21CIP1. These studies identify a new bipartite pathway for activation of beta-cell proliferation, suggesting several new targets for expansion of functional beta-cell mass. We set up a microarray using primary rat islets that were left untreated or transduced with adenoviruses overexpressing betagal or Nkx6.1 for 48 h.
2014-02-18 | E-GEOD-55077 | biostudies-arrayexpress
Project description:Loss of functional β-cell mass is a hallmark of Type 1 and Type 2 diabetes, and methods for restoring these cells are needed. We have previously reported that overexpression of the homeodomain transcription factor Nkx6.1 in rat pancreatic islets induces β-cell proliferation and enhances glucose-stimulated insulin secretion, but the pathway by which Nkx6.1 activates β-cell expansion has not been defined. Here we demonstrate that Nkx6.1 induces expression of the Nr4a1 and Nr4a3 orphan nuclear receptors, and that these factors are both necessary and sufficient for Nkx6.1-mediated β-cell proliferation. Consistent with this finding, global knockout of Nr4a1 results in a decrease in β-cell area in neonatal and young mice. Overexpression of Nkx6.1 and the Nr4a receptors results in increased expression of key cell cycle inducers E2F1 and cyclin E1. Furthermore, Nkx6.1 and Nr4a receptors induce components of the anaphase-promoting complex, including Ube2c, resulting in degradation of the cell cycle inhibitor p21CIP1. These studies identify a new bipartite pathway for activation of β-cell proliferation, suggesting several new targets for expansion of functional β-cell mass.
2014-02-18 | GSE55077 | GEO
Project description:Loss of functional β-cell mass is a hallmark of Type 1 and Type 2 diabetes, and methods for restoring these cells are needed. Nkx6.1 induces β-cell proliferation, but the pathway by which Nkx6.1 activates β-cell expansion has not been defined. Here we demonstrate that Nkx6.1 induces expression of the Nr4a1 and Nr4a3 orphan nuclear receptors, and that these factors are both necessary and sufficient for Nkx6.1-mediated β-cell proliferation. Overexpression of the Nr4a receptors results in increased expression of key cell cycle inducers E2F1 and cyclin E1. Furthermore, Nr4a receptors induce components of the anaphase-promoting complex, including Ube2c.
2014-02-18 | GSE55078 | GEO
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:NR4A nuclear receptors are known tumor suppressors of acute myeloid leukemia and are essential regulators of hematopoietic stem cell (HSC) quiescence. To study the transcriptional consequences of acute NR4A1/3 codepletion in HSCs, we used an Nr4a1/3 conditional knockout mouse model and performed a global transcriptome profiling using RNA-Seq in sorted HSCs four days after NR4A1/3 codepletion.
2018-01-23 | GSE100990 | GEO
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.
2013-12-30 | GSE31042 | GEO
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2020-12-18 | GSE143738 | GEO
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)
2014-02-06 | E-GEOD-54714 | biostudies-arrayexpress