Luminal lncRNAs Regulation by ERα-controlled Enhancers in a Ligand-independent Manner in Breast Cancer Cells
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ABSTRACT:
PROVIDER: PRJNA428309 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6436210_1.fastq.gz | Fastqsanger.gz | |||
| SRR6436210_2.fastq.gz | Fastqsanger.gz | |||
| SRR6436211_1.fastq.gz | Fastqsanger.gz | |||
| SRR6436211_2.fastq.gz | Fastqsanger.gz | |||
| SRR6436206_1.fastq.gz | Fastqsanger.gz |
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Project description:Estrogen receptor-α (ERα) is a ligand-inducible protein which mediates estrogenic hormones signaling and defines the luminal breast cancer phenotype. Recently, we demonstrated that ERα binds chromatin in absence of ligand (apoERα) regulating transcription of protein-coding genes and several lncRNAs. Noteworthy, apoERα-regulated lncRNAs marginally overlap estrogen-induced transcripts representing a signature of luminal breast cancer genes. DSCAM-AS1 is a paradigmatic example of apoERα activity since its expression is largely unaffected by estrogenic treatment despite an E2-induced increment of ERα binding on its promoter. Analysing H3K27ac ChIP-Seq performed in hormone-deprived MCF-7, we identified a set of Super Enhancers (SEs) occupied by apoERα including one mapped in proximity of DSCAM-AS1. Using ChIP-qPCR, we validated ChIP-Seq signal of apoERα, p300 and CTCF at both DSCAM-AS1 TSS and at its associated SE. Furthermore, analysing MCF-7 ChIA-PET data and performing a 3C experiment, we confirmed a long range chromatin interaction between the SE and the DSCAM-AS1 TSS. Interestingly, CTCF binding downstream to DSCAM-AS1 shows an enrichment in hormone-depleted medium as compared to other experimental conditions, indicating that CTCF demarcates enhancer actions at DSCAM-AS1 locus. The analysis of this lncRNA provides a paradigm of transcriptional regulation of a luminal specific apoERα regulated lncRNA.
2018-02-06 | GSE108693 | GEO
Project description:Estrogen receptor-? (ER?) is a ligand-inducible protein which mediates estrogenic hormones signaling and defines the luminal BC phenotype. Recently, we demonstrated that even in absence of ligands ER? (apoER?) binds chromatin sites where it regulates transcription of several protein-coding and lncRNA genes. Noteworthy, apoER?-regulated lncRNAs marginally overlap estrogen-induced transcripts, thus representing a new signature of luminal BC genes. By the analysis of H3K27ac enrichment in hormone-deprived MCF-7 cells, we defined a set of Super Enhancers (SEs) occupied by apoER?, including one mapped in proximity of the DSCAM-AS1 lncRNA gene. This represents a paradigm of apoER? activity since its expression is largely unaffected by estrogenic treatment, despite the fact that E2 increases ER? binding on DSCAM-AS1 promoter. We validated the enrichment of apoER?, p300, GATA3, FoxM1 and CTCF at both DSCAM-AS1 TSS and at its associated SE by ChIP-qPCR. Furthermore, by analyzing MCF-7 ChIA-PET data and by 3C assays, we confirmed long range chromatin interaction between the SE and the DSCAM-AS1 TSS. Interestingly, CTCF and p300 binding showed an enrichment in hormone-depleted medium and in the presence of ER?, elucidating the dynamics of the estrogen-independent regulation of DSCAM-AS1 expression. The analysis of this lncRNA provides a paradigm of transcriptional regulation of a luminal specific apoER? regulated lncRNA.
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Project description:Estrogen receptor alpha (ERα) is a ligand dependent transcription regulator, which contains two transactivation functional domains, AF-1 and AF-2. These activities are regulated differently by the ligands. Specifically, the selective estrogen receptor modulators (SERMs) regulate AF-1 rather than AF-2. It is important to know whether AF-1/AF-2 predominantly regulated genes exist in the tissues for a better understanding of the SERMs functionality. We sought out AF-1 dependent estrogenic genes by using the AF-2 mutated knock-in (KI) mouse model, AF2ERKI. AF2ER is an estrogen-insensitive AF-2 disrupted ERα mutant mouse but unique to this model, AF-1 can be activated by the estrogen-antagonists, such as fulvestrant (ICI) and 4-hydroxytamoxifen (Tam) in vitro and in vivo. The information of genome-wide ICI or Tam dependent AF-2 mutated ERα binding sites could explain the mechanism of the selective estrogenic action of SERMs through AF-1 dependent gene regulation.
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Project description:Dysregulated estrogen and estrogen receptor (ER)-induced gene transcription is tightly associated with estrogen receptor alpha (ERα)-positive breast carcinogenesis. ERα-occupied enhancers, particularly super enhancers, have been suggested to play a vital role in such transcriptional events. However, the landscape of ERα-occupied super enhancers (ERSEs) as well as key super enhancer-associated genes remain to be fully characterized. Here, we defined the landscape of ERSEs in MCF7, a ERα-positive breast cancer cell line, and demonstrated that bromodomain protein BRD4 is a master regulator of the transcriptional activation of ERSE and cognate ERα-target genes. Furthermore, RET, a member of the tyrosine protein kinase family of proteins, was identified to be a key target gene of BRD4-regulated ERSEs, which is vital for estrogen/ ERα-induced gene transcriptional activation and malignant phenotypes through activating the Ras-Raf-MEK-ERK-p90RSK-ERα phosphorylation cascade. Accordingly, combination therapy with BRD4 and RET inhibitors exhibited synergistic effects on suppressing ERα-positive breast cancer both in vitro and in vivo. Taken together, our data uncovered the critical role of a super enhancer-associated BRD4/ERα-RET-ERα positive feedback loop in ERα-positive breast cancer, and targeting components in this loop will provide new therapeutic avenue for treating ERα-positive breast cancer in the clinic.
2022-10-19 | GSE186645 | GEO
Project description:Dysregulated estrogen and estrogen receptor (ER)-induced gene transcription is tightly associated with estrogen receptor alpha (ERα)-positive breast carcinogenesis. ERα-occupied enhancers, particularly super enhancers, have been suggested to play a vital role in such transcriptional events. However, the landscape of ERα-occupied super enhancers (ERSEs) as well as key super enhancer-associated genes remain to be fully characterized. Here, we defined the landscape of ERSEs in MCF7, a ERα-positive breast cancer cell line, and demonstrated that bromodomain protein BRD4 is a master regulator of the transcriptional activation of ERSE and cognate ERα-target genes. Furthermore, RET, a member of the tyrosine protein kinase family of proteins, was identified to be a key target gene of BRD4-regulated ERSEs, which is vital for estrogen/ ERα-induced gene transcriptional activation and malignant phenotypes through activating the Ras-Raf-MEK-ERK-p90RSK-ERα phosphorylation cascade. Accordingly, combination therapy with BRD4 and RET inhibitors exhibited synergistic effects on suppressing ERα-positive breast cancer both in vitro and in vivo. Taken together, our data uncovered the critical role of a super enhancer-associated BRD4/ERα-RET-ERα positive feedback loop in ERα-positive breast cancer, and targeting components in this loop will provide new therapeutic avenue for treating ERα-positive breast cancer in the clinic.
2022-10-19 | GSE186644 | GEO
Project description:Dysregulated estrogen and estrogen receptor (ER)-induced gene transcription is tightly associated with estrogen receptor alpha (ERα)-positive breast carcinogenesis. ERα-occupied enhancers, particularly super enhancers, have been suggested to play a vital role in such transcriptional events. However, the landscape of ERα-occupied super enhancers (ERSEs) as well as key super enhancer-associated genes remain to be fully characterized. Here, we defined the landscape of ERSEs in MCF7, a ERα-positive breast cancer cell line, and demonstrated that bromodomain protein BRD4 is a master regulator of the transcriptional activation of ERSE and cognate ERα-target genes. Furthermore, RET, a member of the tyrosine protein kinase family of proteins, was identified to be a key target gene of BRD4-regulated ERSEs, which is vital for estrogen/ ERα-induced gene transcriptional activation and malignant phenotypes through activating the Ras-Raf-MEK-ERK-p90RSK-ERα phosphorylation cascade. Accordingly, combination therapy with BRD4 and RET inhibitors exhibited synergistic effects on suppressing ERα-positive breast cancer both in vitro and in vivo. Taken together, our data uncovered the critical role of a super enhancer-associated BRD4/ERα-RET-ERα positive feedback loop in ERα-positive breast cancer, and targeting components in this loop will provide new therapeutic avenue for treating ERα-positive breast cancer in the clinic.
2022-10-19 | GSE186643 | GEO
Project description:Genome-wide mapping of ligand-dependent ERα binding sites in the ERα AF-2 mutant mouse uterus
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Project description:Estrogen receptor (ERα) is central in driving the development of hormone-dependent breast cancers. A major challenge in treating these cancers is to understand and struggle endocrine resistance. We have previously shown that the Megakaryoblastic Leukemia 1 (MKL1) protein, a master regulator of actin dynamic and cellular motile functions, directs down-regulation of ERα and hormonal escape of estrogen-responsive breast cancer cell lines. In the present study, we decipher the underlining mechanisms by tracking functional changes in ERα activity. We demonstrate through gene expression microarray analysis that the constitutive activation of MKL1 in ERα-positive MCF7 breast cancer cells induces a transition from a luminal to a basal-like phenotype and suppresses almost all regulations of gene expression by estrogen. Chromatin immunoprecipitation of DNA coupled to high-throughput sequencing (ChIP-Seq) shows a profound reprogramming in ERα cistrome associated with a massive loss of ERα binding sites (ERBSs) generally associated with lower ERα-binding activity. Novel ERBSs appear to be associated with EGF and RAS signaling pathways. ERα dynamic was further impacted by a displacement of its monomer/dimer equilibrium towards its monomer state, associated with a redistribution of the normally nuclear ERα protein to the entire cell volume. We next show that the combination of these remodeled dynamics of ERα alters its interactions with genomic and non-genomic partners. In particular, the formation of ERα/kinase complexes was promoted by the constitutive activation of MKL1. Hence, MKL1-induced transition of ER-positive breast cancer cells from luminal to basal-like phenotype shifts ERα activities from genomic to non-genomic function.
2019-09-11 | GSE107924 | GEO
Project description:ERα is one of the most important transcription factors and therapeutic targets in breast cancer. The patterns of ERα expression in normal breast tissue and cancerous lesions are strikingly different. What drives the change of ERα pattern during lesions formation remains unclear. Here, we describe a novel regulatory mechanism through which miR-200c/141 regulates the level as well as the distribution of ERα in the mammary gland. miR-200c/141 is specifically expressed in luminal cells. Luminal-deletion of miR-200c/141 (miR-cKO) leads to a drastic expansion of ERα+ cell proportion. Single cell RNAseq reveals that miR-cKO generates aberrant luminal subpopulations with increased proliferative and anti-apoptotic features. In vivo lineage tracing of ER- luminal cells demonstrates that miR-200c/141 deletion can convert ER- cells into ER+ cells, which contribute partly to the increase of ERα+ luminal cells. Mechanistic study identifies Ccnd1 as a novel target of miR-200c/141 . Upon miR-200c/141deletion, elevated Ccnd1 level corroborates ERα transcriptional activation, leads to enhanced ERα signaling activity, consequently increased transcription of ERα coding gene Esr1 through self-activation at promoter E1. Our findings reveal a new miR-200c/141-Ccnd1-ERα axis, and provide new molecular insights into how miR-200c/141-Ccnd1 enforces the lineage barrier between ER- and ER+ luminal cells, and what drives the change of ERα expression pattern.
2021-05-05 | GSE173815 | GEO
Project description:ERα is one of the most important transcription factors and therapeutic targets in breast cancer. The patterns of ERα expression in normal breast tissue and cancerous lesions are strikingly different. What drives the change of ERα pattern during lesions formation remains unclear. Here, we describe a novel regulatory mechanism through which miR-200c/141 regulates the level as well as the distribution of ERα in the mammary gland. miR-200c/141 is specifically expressed in luminal cells. Luminal-deletion of miR-200c/141 (miR-cKO) leads to a drastic expansion of ERα+ cell proportion. Single cell RNAseq reveals that miR-cKO generates aberrant luminal subpopulations with increased proliferative and anti-apoptotic features. In vivo lineage tracing of ER- luminal cells demonstrates that miR-200c/141 deletion can convert ER- cells into ER+ cells, which contribute partly to the increase of ERα+ luminal cells. Mechanistic study identifies Ccnd1 as a novel target of miR-200c/141 . Upon miR-200c/141deletion, elevated Ccnd1 level corroborates ERα transcriptional activation, leads to enhanced ERα signaling activity, consequently increased transcription of ERα coding gene Esr1 through self-activation at promoter E1. Our findings reveal a new miR-200c/141-Ccnd1-ERα axis, and provide new molecular insights into how miR-200c/141-Ccnd1 enforces the lineage barrier between ER- and ER+ luminal cells, and what drives the change of ERα expression pattern.
2021-05-05 | GSE173816 | GEO