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Project description:Melanoma is a highly metastatic tumor type responsible of the large majority of the skin cancer-related deaths. Melanoma cells recapitulate the migratory and invasive nature of neural crest stem cells from which melanocytes arise. However, the mechanisms by which these developmental programs confer melanoma cells with more aggressive properties are not understood. Here we provide evidence for an epigenetically regulated developmental program that is aberrantly re-activated by melanoma cells to aid in the metastatic process. We reasoned that studying molecular changes occurring during the ontogeny of melanocytes from progenitor neural crest cells (NCC), and identifying developmental programs retained or re-gained by melanoma cells, could reveal crucial processes that modulate melanoma aggressiveness. Here we describe a novel mechanism that controls the activity of a transcriptional regulator of human neural crest, the Nuclear Receptor Subfamily 2 Group F, Member 2 (NR2F2). We find that highly localized DNA methylation acts as an on/off switch that controls the expression of a truncated NR2F2 isoform (NR2F2-Iso2) from an alternative transcription start site during NCC to melanocyte differentiation. We show that melanoma cells co-opt this developmental program by decreased DNA methylation and re-expression of NR2F2-Iso2 to promote melanoma metastasis. NR2F2-Iso2 regulates the transcriptional activity of the full length NR2F2 isoform 1 by impairing its binding to chromatin, which results in altered expression of NCC and differentiation genes. Our data demonstrate that epigenetic reactivation of NR2F2 isoform 2 promotes melanoma metastasis, which could be targeted for therapeutic purposes.
2023-02-12 | GSE102552 | GEO
Project description:ERα binding activity largely depends on access to binding sites on chromatin, which is facilitated in part by Pioneer Factors (PFs).We show that most binding events of NR2F2 occur together with the ERα binding sites.To explore whether NR2F2 may act as potential pioneer factor of ER, we performed a series of ChIP-seq genome wide in MCF-7. Since NR2F2 associates with chromatin prior to estrogen treatment and its depletion in MCF-7 cells did not affect ERα expression, we hypothesize NR2F2 may inhibit estrogen-dependent growth by modulating ERα recruitment. We performed ChIP-seq genome wide gainst ERα before and after NR2F2 depletion.Covalent modifications are a main chromatin property.To test whether NR2F2 favoured histone modification deposition on chromatin, we profiled ChIP-Seq of H3K4me1, H3K4me3, and H3K27ac following NR2F2 depletion in oestrogen-starved MCF-7 cells to gain comprehensive histone medication landscape.
2019-10-15 | GSE132432 | GEO
Project description:Analysis of NR2F2 knockdown at whole genome level Total RNA isolated 48 hours after NR2F2 knockdown with siRNA compared to siRNA with non-targeting control
2013-05-29 | E-GEOD-47438 | biostudies-arrayexpress
Project description:We focused on NR2F1 and NR2F2 (CoupTF1/CoupTF2) since they are expressed from neural crest through Schwann cell maturity, and found that knockdown of nuclear receptors Nr2f1 and Nr2f2 in primary Schwann cells downregulated genes such as Myelin Basic Protein (Mbp), Desert Hedgehog (Dhh), and N-Myc Downstream Regulated 1 (Ndrg1). In this study, we have elucidated a NR2F-regulated target gene network in Schwann cells, which revealed enrichment for non-myelinating Schwann cell genes. We used Cut&Run in S16 Schwann cells to show novel, genome-wide binding sites of NR2F1/2 and downstream transcription factors, YY1, SREBP1, Retinoid X Receptor (RXRG) and TEA-Domain factor (TEAD1). Our study elucidates the transcriptional cooperation that forms unique enhancer landscapes and the regulatory network that targets non-myelinating Schwann cells.
2024-01-01 | GSE247955 | GEO
Project description:The Alternative Lengthening of Telomeres (ALT) facilitates telomere lengthening by a DNA strand invasion and copying mechanism. The nuclear receptor NR2F2 can bind to (TCAGGG)n variant repeats within telomeres and it has been proposed that this facilitates telomere interactions in ALT+ cells. However, the role NR2F2 in regulation the gene expression in ALT+ cell lines is unclear. Here, using Next Generation Sequencing (NGS), we characterised the changes in expression profile of three ALT+ cell lines (W-V, WI38VA13/2RA, U2OS) upon transient siRNA mediated downregulation of NR2F2 compared to cells treated with a control siRNA . Among 86 ALT-associated genes, only MND1 showed consistent down-regulation across the three NR2F2-depleted ALT+ cell lines. Altogether our data indicate that NR2F2 it does not play a direct role in the ALT mechanism.
2020-12-15 | E-MTAB-9599 | biostudies-arrayexpress
Project description:Gene expression profiles of primary lymphatic endothelial cells (LECs) isolated from human foreskin were analyzed after siRNA-mediated knockdown of control (firefly luciferase), Prox1, NR2F2 or Prox1/NR2F2 for 48 hours. Experiment Overall Design: Passage five human lymphatic endothelial cells (LECs) were cultured on fibronectin (10 μg/ml)-coated plates in a complete media (EBM, 20% FBS supplemented with 10 μg/ml hydrocortisone acetate, 25 ug/ml cAMP and antibiotics). LECs were harvested and electorporated with siRNA duplexes for 48 hours with siRNA duplexes against either firefly luciferase(control), Prox1, NR2F2 or Prox1/NR2F2. Total RNA was purified using Tri-reagent and was subjected to microarray analysis. Experiment Overall Design:
2008-10-25 | E-GEOD-12846 | biostudies-arrayexpress
Project description:Orphan nuclear receptor chicken ovalbumin upstream promoter transcription factor 2 (COUPTF2; NR2F2) is highly expressed in endothelial cells (ECs) and Nr2f2 knockout produces lethal cardiovascular defects. In humans, NR2F2 mutations result in both congenital heart disease and diaphragmatic hernia, conditions associated with the development of pulmonary arterial hypertension (PAH). However, COUPTF2 functions in mature endothelium are uncertain. NR2F2 knockdown in primary human endothelial cells (ECs) led to an interferon-biased inflammatory response, endothelial-to-mesenchymal transition, proliferation, hypermigration, apoptosis-resistance and mitochondrial dysfunction. These phenotypic changes were associated with AKT activation and increased Dickkopf-1 (DKK1) expression, a Wnt/β-catenin pathway inhibitor. DKK1 was also elevated in patients with PAH and secreted in response to loss of bone morphogenetic receptor type 2 (BMPR2), the archetypal PAH-associated genetic defect. Together, these findings demonstrate that endothelial NR2F2 suppresses inflammation and proliferation. Thus, NR2F2 loss disrupts EC homeostasis and may promote pathologic vascular remodeling in the development of PAH.
2023-05-31 | GSE188465 | GEO
Project description:NF1 loss-of-function mutations are enriched in hormone receptor positive (HR+) metastatic breast cancer (MBC) and mediate endocrine therapy resistance. To identify therapeutic vulnerabilities in this context, we performed CRISPR/Cas9 screens in wildtype and NF1 knockout isogenic HR+ models and identified NR2F2, an orphan nuclear receptor, to be essential specifically in NF1 loss cells. The NR2F2 dependence was induced as a consequence of NR2F2 upregulation via the activation of the MAPK pathway in these cells. Enforced overexpression of NR2F2 was sufficient to confer endocrine therapy resistance in the absence of NF1 loss, while of NR2F2 knockout or knockdown could enhance the efficacy of endocrine therapies in NF1 WT and NF1 loss models. Mechanistically, our comprehensive multi-omics approaches revealed that NR2F2 modulates chromatin accessibility and regulates ER-dependent transcription through its interaction with ER, transcriptional coregulators and chromatin remodelers at chromatin. Specifically, increased NR2F2 in NF1 loss cells dramatically enhanced the association with transcriptional corepressors, which resulted in attenuation of chromatin accessibility and ER occupancy, and impaired ER transcriptional program. Our findings identify the nuclear receptor NR2F2 as a downstream effector of NF1 loss, and it is essential and potentially druggable mediator of endocrine therapy resistance. We performed chromatin accessibility profiling analysis using data obtained from ATAC-seq of MCF7 sgNT, sgNF1, sgNR2F2 and double knockout (DKO) cells.
2022-11-10 | GSE217415 | GEO
Project description:We show that most binding events of NR2F2 occur together with the ERα binding sites.To address the functional relationship between NR2F2 and ERα, we assessed the role of NR2F2 in oestrogen-induced growth in ER positive cell line MCF-7. The MTT experiment showed that inhibition of NR2F2 prevented the oestrogen-induced proliferation of MCF-7 cells.To further explore the effect of NR2F2 on estrogen response, We expanded our knockdown studies by performing RNA-seq analysis for MCF-7 cells transfected with control or NR2F2 shRNAs with or without E2.
2019-10-15 | GSE132433 | GEO
Project description:Melanoma is a highly metastatic tumor type responsible of the large majority of the skin cancer-related deaths. Melanoma cells recapitulate the migratory and invasive nature of neural crest stem cells from which melanocytes arise. However, the mechanisms by which these developmental programs confer melanoma cells with more aggressive properties are not understood. Here we provide evidence for an epigenetically regulated developmental program that is aberrantly re-activated by melanoma cells to aid in the metastatic process. We reasoned that studying molecular changes occurring during the ontogeny of melanocytes from progenitor neural crest cells (NCC), and identifying developmental programs retained or re-gained by melanoma cells, could reveal crucial processes that modulate melanoma aggressiveness. Here we describe a novel mechanism that controls the activity of a transcriptional regulator of human neural crest, the Nuclear Receptor Subfamily 2 Group F, Member 2 (NR2F2). We find that highly localized DNA methylation acts as an on/off switch that controls the expression of a truncated NR2F2 isoform (NR2F2-Iso2) from an alternative transcription start site during NCC to melanocyte differentiation. We show that melanoma cells co-opt this developmental program by decreased DNA methylation and re-expression of NR2F2-Iso2 to promote melanoma metastasis. NR2F2-Iso2 regulates the transcriptional activity of the full length NR2F2 isoform 1 by impairing its binding to chromatin, which results in altered expression of NCC and differentiation genes. Our data demonstrate that epigenetic reactivation of NR2F2 isoform 2 promotes melanoma metastasis, which could be targeted for therapeutic purposes.
2023-02-12 | GSE102553 | GEO