NR2E3 gene networks are associated with AHR signaling pathways
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE79463 | GEO | 2017/10/31
SECONDARY ACCESSION(S): PRJNA315878
REPOSITORIES: GEO
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2011-12-22 | GSE18431 | GEO
Project description:While the roles of individual nuclear receptor (NR) in human diseases have been well characterized, interplays among NRs have not been extensively characterized due, in part, to technical difficulties in simultaneously monitoring molecular activities of all 48 NR genes. Using systems-level analysis of publically available gene expression data from NCI-60 cell lines, we uncovered novel interaction between ESR1 and orphan receptor NR2E3. Expression of NR2E3 is significantly associated with expression of ESR1 in NCI-60 cell lines as well as in breast cancer patients. To investigate how NR2E3 gene signatures are globally correlated with ESR1 signaling pathway, we performed microarray after knocking down NR2E3 or ESR1 in MCF-7 cells. Keywords: DNA microarray (Illumina human Ht12 V3) 3 shControl, 3 shNR2E3, 3 siLuc, 3 siESR1
2011-12-22 | E-GEOD-18431 | biostudies-arrayexpress
Project description:The orphan nuclear receptor NR2E3 (Nuclear receptor subfamily 2 group E, Member 3) is an epigenetic player essential for p53 activation during liver injuries through its modulation of chromatin accessibility. Nonetheless, a precise tumor suppressive and epigenetic role of NR2E3 in hepatocellular carcinoma (HCC) remains unclear. HCC patients expressing low NR2E3 exhibit unfavorable clinical outcomes, aligning with heightened activation of the WNT/β-catenin signaling pathway. The murine HCC models utilizing NR2E3 knockout mice consistently exhibits accelerated liver tumor formation and progression accompanied by enhanced activation of WNT/β-catenin signaling pathway and inactivation of p53 signaling pathway. At cellular level, the loss of NR2E3 increases the acquisition of aggressive cancer cell phenotype and tumorigenicity and upregulates key genes in the WNT/β-catenin pathway with enhanced chromatin accessibility. This event is mediated through increased formation of active transcription complex involving Sp1, β-catenin, and p300, a histone acetyltransferase, on the promoters of target genes. These findings demonstrate that the loss of NR2E3 promotes WNT/β-catenin signaling activation at cellular, organismal, and clinical levels. In summary, NR2E3 is a novel tumor suppressor that maintains epigenetic homeostasis, thereby preventing activation of WNT/β-catenin signaling that promotes HCC formation and progression.
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Project description:We previously reported that the nuclear receptor NR2E3 activates the tumor suppressor gene p53 by modulating chromatin accessibility. In this study, we further investigated the impact of NR2E3 deficiency on chromatin accessibility. We used FAIRE-seq (Formaldehyde-Assisted Isolation of Regulatory Elements) analysis to find that NR2E3 loss increased chromatin accessibility in genomic regions interacting with various transcription factors, including Sp1. Additionally, NR2E3 loss enhanced chromatin accessibility and expression of crucial genes, such as JAK1 and PPARD, essential for WNT-β-catenin signaling pathway activation by facilitating interactions between Sp1 and Myc transcription factors at their promoters. Gene set enrichment analysis (GSEA) on mouse liver tumor tissues from wild-type and NR2E3 knockout mice confirmed that NR2E3 ablation activated WNT-β-catenin signaling pathways in vivo. Kaplan-Meier survival analysis using liver cancer patient data from two clinical datasets confirmed that patients with low NR2E3 expression exhibited increased WNT-β-catenin signaling activation, associated with adverse clinical outcomes. These findings highlight NR2E3 as a crucial tumor suppressor gene in hepatocellular carcinoma (HCC), primarily restraining WNT-β-catenin signaling pathway activation to maintain epigenetic homeostasis and contribute to HCC development. Our results prove NR2E3's critical role in liver cancer pathogenesis by regulating WNT-β-catenin signaling pathways and epigenetic equilibrium maintenance. The Formaldehyde Assisted Isolation of Regulatory Elemens (FAIRE)-Seqwas performed using control (shCT) and NR2E3-depleted (shNR2E3) HepG2 cells.
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Project description:Rod and cone photoreceptors in mammalian retina are generated from common pool(s) of neuroepithelial progenitors. NRL, CRX and NR2E3 are key transcriptional regulators that control photoreceptor differentiation. Mutations in NR2E3, a rod-specific orphan nuclear receptor, lead to loss of rods, increased density of S-cones, and supernormal S-cone-mediated vision in humans. To better understand its in vivo function, NR2E3 was expressed ectopically in the Nrl-/- retina, where post-mitotic precursors fated to be rods develop into functional S-cones similar to the human NR2E3 disease. Expression of NR2E3 in the Nrl-/- retina completely suppressed cone differentiation and resulted in morphologically rod-like photoreceptors, which were not functional. Gene profiling of FACS-purified photoreceptors confirmed the role of NR2E3 as a strong suppressor of cone genes and an activator of a subset of rod genes (including rhodopsin) in vivo. Ectopic expression of NR2E3 in cone precursors and differentiating S-cones of wild type retina also generates rod-like cells. The dual regulatory function of NR2E3 is not dependent upon the presence of NRL and/or CRX, but on the timing and level of its expression. Our studies reveal a critical role of NR2E3 in establishing functional specificity of post-mitotic photoreceptor precursors during retinal neurogenesis. Experiment Overall Design: We mated the Crx::Nr2e3/Nrlko mice with the Nrl::GFP transgenic mice, in which the expression of GFP is driven by an Nrl promoter. Mouse retinas were dissected at 4 wk. GFP+ photoreceptors were enriched by FACS (FACSAria, BD Biosciences, Franklin Lakes, NJ). RNA was extracted from 1~5x105 flow-sorted cells using Trizol (Invitrogen). Total RNA (40-60 ng) was used for linear amplification with Ovation Biotin labeling system (Nugen), and 2.75 ug of biotin-labeled fragmented cDNA was hybridized to mouse GeneChips MOE430.2.0 (Affymetrix) having 45,101 probesets (corresponding to over 39,000 transcripts, and 34,000 annotated mouse genes). Experiment Overall Design: Four independent samples were used at 4 weeks. We normalized Experiment Overall Design: Crx::Nr2e3/Nrl-ko-Gfp data along with Nrl-ko-Gfp 4 weeks samples ( 4 replicates, refer to Series submission GSE4051). The normalized data was then subjected to two stage analysis based on False Discovery Rate Confidence Interval (FDR-CI) for screening differentially expressed genes (24, 27) with a minimum fold change of 4.
2008-06-13 | E-GEOD-5338 | biostudies-arrayexpress
Project description:Single-cell RNA-seq of mouse WT retinas and two Nr2e3 mutant retinas, ∆27 and ∆E8 (containing a 27 nucleotide in-frame deletion or a complete exon 8 deletion, respectively). The ∆27 retinas were used as a model for enhanced S-cone syndrome phenotype in humans, while the ∆E8 retinas show a progressive retinal degeneration similar to human retinitis pigmentosa patients. This data was used to explore the role of Nr2e3 in cone and rod photoreceptor differentiation.
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Project description:We previously reported that the nuclear receptor NR2E3 activates the tumor suppressor gene p53 by modulating chromatin accessibility. In this study, we further investigated the impact of NR2E3 deficiency on chromatin accessibility. We used FAIRE-seq (Formaldehyde-Assisted Isolation of Regulatory Elements) analysis to find that NR2E3 loss increased chromatin accessibility in genomic regions interacting with various transcription factors, including Sp1. Additionally, NR2E3 loss enhanced chromatin accessibility and expression of crucial genes, such as JAK1 and PPARD, essential for WNT-β-catenin signaling pathway activation by facilitating interactions between Sp1 and Myc transcription factors at their promoters. Gene set enrichment analysis (GSEA) on mouse liver tumor tissues from wild-type and NR2E3 knockout mice confirmed that NR2E3 ablation activated WNT-β-catenin signaling pathways in vivo. Kaplan-Meier survival analysis using liver cancer patient data from two clinical datasets confirmed that patients with low NR2E3 expression exhibited increased WNT-β-catenin signaling activation, associated with adverse clinical outcomes. These findings highlight NR2E3 as a crucial tumor suppressor gene in hepatocellular carcinoma (HCC), primarily restraining WNT-β-catenin signaling pathway activation to maintain epigenetic homeostasis and contribute to HCC development. Our results prove NR2E3's critical role in liver cancer pathogenesis by regulating WNT-β-catenin signaling pathways and epigenetic equilibrium maintenance. RNA-seq with WT and NR2E3 KO Liver Tumors
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