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Transcriptional profiling of monocytes deficient in Nuclear Orphan Receptors NR4A2 and NR4A3 reveals distinct signalling roles related to antigen presentation and viral response.

ABSTRACT: Transcriptional profiling of monocytes deficient in Nuclear Orphan Receptors NR4A2 and NR4A3 reveals distinct signalling roles related to antigen presentation and viral response.

PROVIDER: PRJNA738860 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14853827_1.fastq.gz	Fastqsanger.gz
	SRR14853827_2.fastq.gz	Fastqsanger.gz
	SRR14853828_1.fastq.gz	Fastqsanger.gz
	SRR14853828_2.fastq.gz	Fastqsanger.gz
	SRR14853829_1.fastq.gz	Fastqsanger.gz

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Transcriptional profiling of monocytes deficient in Nuclear Orphan Receptors NR4A2 and NR4A3 reveals distinct signalling roles related to antigen presentation and viral response.

Project description:Using RNA-sequencing and strategic bioinformatic analysis we investigated the down-stream effects of NR4A2 and NR4A3 in monocytes and dissected their common and distinct signalling roles.NR4A2 selective genes were most associated with antigen presentation, NR4A3 selective genes were most associated with interferon/viral reponse and NR4A2/3 co-regulated genes were most associated with clasical innate immure response signaling e.g. TLR signaling and chemokine secretion.

2021-06-18 | GSE178391 | GEO

NR4A1 and NR4A2 orphan nuclear receptors regulate endothelial to hematopoietic transition in mouse hematopoietic stem cell specification

Project description:Hematopoietic stem cells (HSCs) sustain life-long hematopoiesis and emerge during mid-gestation from hemogenic endothelial (HE) progenitors via an endothelial to hematopoietic transition (EHT). The full scope of molecular mechanisms governing this process remains unclear. The NR4A subfamily of orphan nuclear receptors act as tumour suppressors in myeloid leukemogenesis and have never been implicated in HSC specification. Here, we report that Nr4a1 and Nr4a2 expression is upregulated in hemogenic endothelium during EHT. Progressive genetic ablation of Nr4a gene dosage results in a gradual decrease in numbers of nascent c-Kit+ hematopoietic progenitors in developing embryos, c-Kit+ cell cluster size in the dorsal aorta, and a block in HSC maturation, revealed by an accumulation of pro-HSCs and pre-HSC-type I cells and decreased numbers of pre-HSC-type II cells. Consistent with these observations, cells isolated from E11.5 Nr4a1-/-; Nr4a2-/- aorta-gonads-mesonephros (AGM) are devoid of in vivo long-term hematopoietic repopulating potential. Molecularly, employing spatial transcriptomic analysis we determined that the genetic ablation of Nr4a1 and Nr4a2 prevents NOTCH signaling from being downregulated in intra-aortic clusters and thus for pro-HSCs to mature into HSCs. Interestingly, this defect is partially rescued via ex vivo culture of dissected AGMs with SCF, IL3 and FLT3L, which may bypass NOTCH-dependent regulation. Overall, our data reveal a novel role for the NR4A family of orphan nuclear receptors in EHT.

2024-11-04 | GSE281058 | GEO

NR4A2 and NR4A3 selectively modulate elements of the monocyte response to buffered hypercapnia

Project description:In wild type, NR4A2-deficient, and NR4A3-deficient monocytes we used RNA-sequencing to investigate the effect of 4hrs of exposure to buffered hypercapnia (10% CO2) compared to normocapnia (5% CO2) with and without the pro-inflammatory stimulus LPS (2.5ug/ml) for the final 2hrs. Buffered hypercapnia causes transcriptional changes associated with altered metabolic function in both the basal and stimulated states.

2024-03-20 | GSE251925 | GEO

The orphan nuclear receptor NR4A3 is involved in the function of dendritic cells

Project description:Transcriptome analysis of LPS-stimulated bone marrow-derived dendritic cells with NR4A3 gene silencing The NR4A3/NOR1 belongs to the NR4A subfamily of the orphan nuclear hormone receptor superfamily, which is activated in a ligand-independent manner. To examine the role of NR4A3/NOR1 in gene expression of dendritic cells (DCs), we introduced NR4A3 siRNA into bone marrow-derived DCs (BMDCs) and determined the expression levels of mRNA and proteins of cytokines, cell surface molecules, NFκB signaling-related proteins, and transcription factors. The expression level of NR4A3 was markedly up-regulated by TLRs-mediated stimulation in DCs. NR4A3 knockdown significantly suppressed LPS, CpG, or poly I:C-mediated up-regulation of CD80, CD86, IL-10, IL-6, and IL-12. Proliferation and IL-2 production levels of T cells co-cultured with NR4A3-knocked down DCs were significantly lower than that of T cells co-cultured with control DCs. Furthermore, the expression of IKKβ, IRF4, and IRF8 was significantly decreased in NR4A3 siRNA-introduced BMDCs. The knockdown experiments using siRNAs for IKKβ, IRF4, and/or IRF8 indicated that LPS-induced up-regulation of IL-10 and IL-6 was reduced in IKKβ knocked down cells, and that the up-regulation of IL-12 was suppressed by the knockdown of IRF4 and IRF8. Taken together, these results indicate that NR4A3 is involved in TLR-mediated activation and gene expression of DCs.

2017-10-01 | GSE101831 | GEO

Nkx6.1 regulates islet beta-cell proliferation via Nr4a1 and Nr4a3 nuclear receptors

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

NR4A1 and NR4A2 orphan nuclear receptors regulate endothelial to hematopoietic transition in mouse hematopoietic stem cell specification

Project description:NR4A1 and NR4A2 orphan nuclear receptors regulate endothelial to hematopoietic transition in mouse hematopoietic stem cell specification

| PRJNA1181898 | ENA

Nr4a1 and Nr4a3 upregulate cell cycle genes upregulated in the Nkx6.1 beta-cell proliferation pathway

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 Î²-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

Nkx6.1 regulates islet β-cell proliferation via Nr4a1 and Nr4a3 nuclear receptors

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

NR2C/F orphan receptors induce telomere-genome rearrangements in ALT

Project description:Most sarcomas have complex karyotype and are characterized by multiple chromosomal rearrangements. Moreover, sarcomas very frequently maintain their telomeres by recombination in the process called Alternative Lengthening of Telomeres (ALT) which enables their continuous growth and immortalization. Previously our group showed that orphan receptors bind specifically to the ALT telomeres and that their presence is important for the ALT mechanism. In these studies we focus on the function of orphan receptors at the telomeres and their contribution to telomeric recombination. We demonstrate that orphan receptors induce proximity of their binding sites in telomeric and genomic context and reveal novel aspects of ALT which are telomere-genome rearrangements which can underlie complexity of sarcomas. Our data perturb the dogma of telomere function in protecting the genome integrity. Here we show that in some cases telomeres may in fact drive genomic instability and chromosomal rearrangements by recombination with genomic sites. Characterization of TRF2 and orphan receptor NR2F/C2 binding sites in ALT (-) and ALT (+) cells.

2015-02-23 | E-GEOD-46237 | biostudies-arrayexpress

NR4A2 and NR4A3 selectively modulate elements of the monocyte response to buffered hypercapnia

Project description:NR4A2 and NR4A3 selectively modulate elements of the monocyte response to buffered hypercapnia

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