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NR4A1 and NR4A3 Restrict HSC Proliferation via Reciprocal Regulation of C/EBPα and Inflammatory Signaling

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE100990 | GEO | 2018/01/23

REPOSITORIES: GEO

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NR4A1 and NR4A3 restrict HSC proliferation via reciprocal regulation of C/EBP? and inflammatory signaling.

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2014-02-18 | E-GEOD-55077 | biostudies-arrayexpress

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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

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Gene expression in anergic and naïve CD4 T cells deficient for Nr4a1 and Nr4a3

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.

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Genome-wide ChIP-seq analysis of Nr4a1 binding sites in regulatory T (Treg) cells

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