NR2F2 melanoma cellular models
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ABSTRACT:
PROVIDER: PRJNA398018 | ENA |
REPOSITORIES: ENA
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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 | GSE102553 | 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 | GSE102552 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-02-10 | GSE102554 | GEO
Project description:Metastatic melanoma develops once transformed melanocytic cells begin to de-differentiate into migratory and invasive melanoma cells with neural crest cell (NCC)-like and epithelial-to mesenchymal transition (EMT)-like features. However, it is still unclear how transformed melanocytes assume a metastatic melanoma cell state. Here, we define DNA-methylation changes that accompany metastatic progression in melanoma patients and discover Nuclear Receptor Subfamily 2 Group F, Member 2 – isoform 2 (NR2F2-Iso2) as an epigenetically regulated metastasis driver. NR2F2-Iso2 is transcribed from an alternative transcriptional start site (TSS) and it is truncated at the N-terminal end which encodes the NR2F2 DNA-binding domain. We find that NR2F2-Iso2 expression is turned off by DNA methylation when NCCs differentiate into melanocytes. Conversely, this process is reversed during metastatic melanoma progression, when NR2F2-Iso2 becomes increasingly hypomethylated and re-expressed. Our functional and molecular studies suggest that NR2F2-Iso2 drives metastatic melanoma progression by modulating the activity of full-length NR2F2 (Isoform 1) over EMT- and NCC associated target genes. Our findings indicate that DNA-methylation changes play a crucial role during metastatic melanoma progression, and their control of NR2F2 activity allows transformed melanocytes to acquire NCC-like and EMT-like features. This epigenetically regulated transcriptional plasticity facilitates cell state transitions and metastatic spread.
2022-12-31 | GSE102542 | GEO
Project description:Metastatic melanoma develops once transformed melanocytic cells begin to de-differentiate into migratory and invasive melanoma cells with neural crest cell (NCC)-like and epithelial-to mesenchymal transition (EMT)-like features. However, it is still unclear how transformed melanocytes assume a metastatic melanoma cell state. Here, we define DNA-methylation changes that accompany metastatic progression in melanoma patients and discover Nuclear Receptor Subfamily 2 Group F, Member 2 – isoform 2 (NR2F2-Iso2) as an epigenetically regulated metastasis driver. NR2F2-Iso2 is transcribed from an alternative transcriptional start site (TSS) and it is truncated at the N-terminal end which encodes the NR2F2 DNA-binding domain. We find that NR2F2-Iso2 expression is turned off by DNA methylation when NCCs differentiate into melanocytes. Conversely, this process is reversed during metastatic melanoma progression, when NR2F2-Iso2 becomes increasingly hypomethylated and re-expressed. Our functional and molecular studies suggest that NR2F2-Iso2 drives metastatic melanoma progression by modulating the activity of full-length NR2F2 (Isoform 1) over EMT- and NCC associated target genes. Our findings indicate that DNA-methylation changes play a crucial role during metastatic melanoma progression, and their control of NR2F2 activity allows transformed melanocytes to acquire NCC-like and EMT-like features. This epigenetically regulated transcriptional plasticity facilitates cell state transitions and metastatic spread.
2022-12-31 | GSE213390 | GEO
Project description:Metastatic melanoma develops once transformed melanocytic cells begin to de-differentiate into migratory and invasive melanoma cells with neural crest cell (NCC)-like and epithelial-to mesenchymal transition (EMT)-like features. However, it is still unclear how transformed melanocytes assume a metastatic melanoma cell state. Here, we define DNA-methylation changes that accompany metastatic progression in melanoma patients and discover Nuclear Receptor Subfamily 2 Group F, Member 2 – isoform 2 (NR2F2-Iso2) as an epigenetically regulated metastasis driver. NR2F2-Iso2 is transcribed from an alternative transcriptional start site (TSS) and it is truncated at the N-terminal end which encodes the NR2F2 DNA-binding domain. We find that NR2F2-Iso2 expression is turned off by DNA methylation when NCCs differentiate into melanocytes. Conversely, this process is reversed during metastatic melanoma progression, when NR2F2-Iso2 becomes increasingly hypomethylated and re-expressed. Our functional and molecular studies suggest that NR2F2-Iso2 drives metastatic melanoma progression by modulating the activity of full-length NR2F2 (Isoform 1) over EMT- and NCC associated target genes. Our findings indicate that DNA-methylation changes play a crucial role during metastatic melanoma progression, and their control of NR2F2 activity allows transformed melanocytes to acquire NCC-like and EMT-like features. This epigenetically regulated transcriptional plasticity facilitates cell state transitions and metastatic spread.
2022-12-31 | GSE213382 | GEO
Project description:RNA-sequencing of NR2F2-isoform 2 melanoma cellular models
| PRJNA398019 | ENA
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: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 ER chromatin binding profiling analysis using data obtained from ChIP-seq of MCF7 sgNT, sgNF1, sgNR2F2 and double knockout (DKO) cells under the conditions of full media, estrogen starvation and estrogen stimulation. We also performed NR2F chromatin binding profiling analysis using data obtained from ChIP-seq of MCF7 sgNT and sgNF1 cells under full media culture condition
2022-11-10 | GSE217416 | GEO