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ERa-related enhancers driven by BAP18-induced chromatin accessibility with CTCF/NURF complex enrichment contributes to aromatase inhibitor non-response in breast cancer (ChIP-seq)

ABSTRACT: Endocrine therapy is the preferred therapeutic strategy for estrogen receptor alpha (ERa)-positive breast cancer, but intrinsic endocrine resistance leads a significant challenge. CCCTC binding factor (CTCF)-mediated hyperactivation of ERa-associated enhancers have been recognized as important molecular mechanism leading to endocrine resistance, yet the underlying molecular mechanism of this process still remains unclear. Here, we found a critical enhancer modulator, Bromodomain PHD Finger Transcription Factor (BPTF) associated protein of 18kDa (BAP18), had a global recruitment on gene enhancer combining with CTCF. Consistently, ERa-related enhancer transactivation was highly correlated with increasing BAP18 enrichment. BAP18 interacted with SMARCA1, another nucleosome remodeling factor (NURF) complex subunit, participating modulating CTCF and ERa recruitment on enhancers. Interestingly, BAP18 globally advantaged chromatin accessibility of enhancer regions, especially the sites with CTCF binding, thereby increasing targeted enhancer-promoter looping (E-P looping) by facilitating CTCF recruitment. Our functional studies in multiple culture and aromatase inhibitor (AI)-nonresponse models reveal a critical role of BAP18 in regulating drug tolerance of breast cancer cells and patients. Collectively, our study suggested that BAP18 coordinated with CTCF in transactivating ERa-related enhancers, and exhibited a better understanding about chromatin remodeling and E-P looping mechanism of AI therapy resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE198242 | GEO | 2022/03/16

REPOSITORIES: GEO

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Project description:Endocrine therapy is the preferred therapeutic strategy for estrogen receptor alpha (ERa)-positive breast cancer, but intrinsic endocrine resistance leads a significant challenge. CCCTC binding factor (CTCF)-mediated hyperactivation of ERa-associated enhancers have been recognized as important molecular mechanism leading to endocrine resistance, yet the underlying molecular mechanism of this process still remains unclear. Here, we found a critical enhancer modulator, Bromodomain PHD Finger Transcription Factor (BPTF) associated protein of 18kDa (BAP18), had a global recruitment on gene enhancer combining with CTCF. Consistently, ERa-related enhancer transactivation was highly correlated with increasing BAP18 enrichment. BAP18 interacted with SMARCA1, another nucleosome remodeling factor (NURF) complex subunit, participating modulating CTCF and ERa recruitment on enhancers. Interestingly, BAP18 globally advantaged chromatin accessibility of enhancer regions, especially the sites with CTCF binding, thereby increasing targeted enhancer-promoter looping (E-P looping) by facilitating CTCF recruitment. Our functional studies in multiple culture and aromatase inhibitor (AI)-nonresponse models reveal a critical role of BAP18 in regulating drug tolerance of breast cancer cells and patients. Collectively, our study suggested that BAP18 coordinated with CTCF in transactivating ERa-related enhancers, and exhibited a better understanding about chromatin remodeling and E-P looping mechanism of AI therapy resistance.

2022-03-16 | GSE198241 | GEO

Dynamic-network-guided CRISPRi screen identifies CTCF loop-constrained 1 nonlinear enhancer-gene regulatory activity in cell state transitions

Project description:Enhancers play key roles in gene regulation. However, comprehensive enhancer discovery is challenging because most enhancers, especially those affected in complex diseases, have weak effects on gene expression. Through gene regulatory network modeling, we identified that dynamic cell state transitions, a critical missing component in prevalent enhancer discovery strategies, can be utilized to improve the cells’ sensitivity to enhancer perturbation. Guided by the modeling results, we performed a mid-transition CRISPRi-based enhancer screen utilizing human embryonic stem cell definitive endoderm differentiation as a dynamic transition system. The screen discovered a comprehensive set of enhancers (4 to 9 per locus) for each of the core lineage-specifying transcription factors (TFs), including many enhancers with weak to moderate effects. Integrating the screening results with enhancer activity measurements (ATAC-seq, H3K27ac ChIP-seq) and three-dimensional enhancer-promoter interaction information (CTCF looping, Hi-C), we were able to develop a CTCF loop-constrained Interaction Activity (CIA) model that can better predict functional enhancers compared to models that rely on Hi-C-based enhancer-promoter contact frequency. Together, our dynamic network-guided enhancer screen and the CIA enhancer prediction model provide generalizable strategies for sensitive and more comprehensive enhancer discovery in both normal and pathological cell state transitions.

2023-06-17 | PXD043070 | Pride

An H3K4me3 reader, BAP18 as an adaptor of COMPASS-like core subunits co-activates ERa action to confer to tamoxifen resistance in breast cancer

Project description:Estrogen receptor alpha (ERalpha signaling pathway is essential for ERalpha positive breast cancer progression and endocrine therapy resistance. BPTF associated protein of 18kDa (BAP18) has been recognized as a crucial H3K4me3 reader. However, the whole genomic occupation of BAP18 and its biological function in breast cancer are still elusive. Here, we found that higher expression of BAP18 in ERalpha positive breast cancer is positively correlated with poor prognosis. ChIP-seq analysis further demonstrated that the half estrogen response elements (EREs) and the CCCTC binding factor (CTCF) binding sites are the significant enrichment sites found in estrogen-induced BAP18 binding sites. In addition, we provide the evidence to demonstrate that BAP18 as a novel co-activator of ERalpha is required for the recruitment of COMPASS-like core subunits to cis-regulatory element of ERalpha target genes in breast cancer cells. BAP18 is recruited to the promoter regions of estrogen-induced genes, accompanied with the enrichment of the lysine 4-trimethylated histone H3 tail (H3K4me3) in the presence of E2. Furthermore, BAP18 promotes cell growth and confers to ERalpha antagonist tamoxifen resistancein ERalpha positive breast cancer. Our data suggest that BAP18 facilitates the association between ERalpha and COMPASS-like core subunits, which might be an essential epigenetic therapeutic target for breast cancer.

2020-11-09 | GSE144641 | GEO

MYSM1 acts as a novel co-activator of ERα via histone and non-histone deubiquitination to confer antiestrogen resistance in breast cancer

Project description:Endocrine resistance is a crucial challenge in estrogen receptor alpha (ERa)-positive breast cancer (BCa). Aberrant alteration in modulation of E2/ERa signaling pathway has emerged as the putative contributor for endocrine resistance in BCa. Herein, we demonstrate that MYSM1 as a deubiquitinase participates in modulating ERa action via histone and non-histone deubiquitination. MYSM1 is involved in maintenance of ERa stability via ERa deubiquitination. Silencing MYSM1 induces enhancement of histone H2A ubiquitination as well as reduction of histone H3K4me3, H3K9ac and H3K27ac levels at cis regulatory elements on promoter of ERa-regulated genes. ChIP-seq analysis indicate that the half-EREs are the significant enrichment sites for MYSM1 on ERa-regulated genes. MYSM1 depletion attenuates cell growth in BCa-derived cell lines and xenograft models. Knockdown of MYSM1 increases the sensitivity of antiestrogen agents in BCa cells. A virtual screen shows that the small molecule Imatinib could potentially interact with catalytic MPN domain of MYSM1 to inhibit BCa cell growth via MYSM1-ERa axis. MYSM1 is highly expressed in clinical BCa samples, especially in aromatase inhibitor (AI) non-responsive tissues. These findings clarify the molecular mechanism of MYSM1 as an epigenetic modifier in regulation of ERa action and provide a potential therapeutic target for endocrine resistance in BCa.

2023-08-08 | GSE240215 | GEO

Enhancer-bound LDB1 Regulates a Corticotrope Promoter Pausing Repression Program [ChIP-seq]

Project description:Substantial evidence supports the hypothesis that enhancers are critical regulators of cell type determination, orchestrating both positive and negative transcriptional programs; however, the basic mechanisms by which enhancers orchestrate interactions with cognate promoters during activation and repression events remain incompletely understood. Here we report the required actions of the LIM domain binding protein, LDB1/CLIM2/NLI, interacting with the enhancer binding protein, ASCL1, to mediate looping to target gene promoters and target gene regulation in corticotrope cells. LDB1-mediated enhancer:promoter looping appears to be required for both activation and repression of these target target gene promoter genes. While LDB1-dependend activated genes are regulated at the level of transcriptional initiation, the LDB1-dependent repressed transcription units appear to be regulated primarily at the level of promoter pausing, with LDB1 regulating recruitment of MTA2, a component of the NuRD complex, on these negative enhancers, required for the repressive enhancer function. These results indicate that LDB1-dependent looping events can deliver repressive cargo to cognate promoters to mediate promoter pausing events in a pituitary cell type. ChIP assay followed by high throughput sequencing (ChIP-seq)

2015-02-03 | E-GEOD-64483 | biostudies-arrayexpress

Enhancer-bound LDB1 Regulates a Corticotrope Promoter Pausing Repression Program [GRO-seq]

Project description:Substantial evidence supports the hypothesis that enhancers are critical regulators of cell type determination, orchestrating both positive and negative transcriptional programs; however, the basic mechanisms by which enhancers orchestrate interactions with cognate promoters during activation and repression events remain incompletely understood. Here we report the required actions of the LIM domain binding protein, LDB1/CLIM2/NLI, interacting with the enhancer binding protein, ASCL1, to mediate looping to target gene promoters and target gene regulation in corticotrope cells. LDB1-mediated enhancer:promoter looping appears to be required for both activation and repression of these target target gene promoter genes. While LDB1-dependend activated genes are regulated at the level of transcriptional initiation, the LDB1-dependent repressed transcription units appear to be regulated primarily at the level of promoter pausing, with LDB1 regulating recruitment of MTA2, a component of the NuRD complex, on these negative enhancers, required for the repressive enhancer function. These results indicate that LDB1-dependent looping events can deliver repressive cargo to cognate promoters to mediate promoter pausing events in a pituitary cell type. Global Run On (GRO) assay followed by high throughput sequencing (GRO-seq)

2015-02-03 | E-GEOD-64515 | biostudies-arrayexpress

Ligand dependent gene regulation by transient ERa clustered enhancers

Project description:Unliganded Estrogen receptor alpha (ERa) has been implicated in ligand-dependent gene regulation. Upon ligand exposure, ERa binds to several EREs relatively proximal to the pre-marked, or persistent, ERa-bound sites and affects transient but robust gene expression. However, the underlying mechanisms are not fully understood. Here we demonstrate that upon ligand stimulation, persistent sites interact extensively, via chromatin looping, with the proximal transiently ERa-bound sites, forming Ligand Dependent ERa Enhancer Cluster in 3D (LDEC). The E2-target genes are regulated by these clustered enhancers but not by the H3K27Ac super-enhancers. Further, CRISPR-based deletion of TFF1 persistent site disrupts the formation of its LDEC resulting in the loss of E2-dependent expression of TFF1 and its neighboring genes within the same TAD. The LDEC overlap with nuclear ERa condensates that coalesce in a ligand and persistent site dependent manner. Furthermore, formation of clustered enhancers, as well as condensates, coincide with the active phase of signaling and their later disappearance results in the loss of gene expression even though persistent sites remain bound by ERa. Our results establish a direct link between ERa condensates, ERa enhancer clusters, and transient, but robust, gene expression in a ligand-dependent fashion.

2019-11-22 | GSE136302 | GEO

COLO829 treatment with PLX4032 and/or MITF knockdown

Project description:Thousands of enhancers are characterized in the human genome, yet few have been shown important in cancer. Inhibiting oncokinases, such as EGFR, ALK, HER2, and BRAF, is a mainstay of current cancer therapy but is hindered by innate drug resistance mediated by upregulation of the HGF receptor, MET. The mechanisms mediating such genomic responses to targeted therapy are unknown. Here, we identify lineage-specific MET enhancers for multiple common tumor types, including a melanoma lineage-specific MET enhancer that displays inducible chromatin looping and MET gene induction upon BRAF inhibition. Epigenomic analysis demonstrated that the melanocyte-specific transcription factor, MITF, mediates this enhancer function. Targeted genomic deletion (<7bp) of the MITF motif within the MET enhancer suppressed inducible chromatin looping and innate drug resistance, while maintaining MITF-dependent, inhibitor-induced melanoma cell differentiation. Epigenomic analysis can thus guide functional disruption of regulatory DNA to decouple pro- and anti-oncogenic functions of tumor lineage-enriched transcription factors mediating innate resistance to oncokinase therapy. COLO829 human melanoma cell line harboring the BRAFV600E mutation was treated with BRAF inhibtior PLX4032 (Vemurafenib) and/or a hairpin against MITF

2014-01-14 | E-GEOD-50649 | biostudies-arrayexpress

MITF ChIP-seq in primary melanocyte and melanoma as a function of oncogenic BRAF

Project description:Thousands of enhancers are characterized in the human genome, yet few have been shown important in cancer. Inhibiting oncokinases, such as EGFR, ALK, HER2, and BRAF, is a mainstay of current cancer therapy but is hindered by innate drug resistance mediated by upregulation of the HGF receptor, MET. The mechanisms mediating such genomic responses to targeted therapy are unknown. Here, we identify lineage-specific MET enhancers for multiple common tumor types, including a melanoma lineage-specific MET enhancer that displays inducible chromatin looping and MET gene induction upon BRAF inhibition. Epigenomic analysis demonstrated that the melanocyte-specific transcription factor, MITF, mediates this enhancer function. Targeted genomic deletion (<7bp) of the MITF motif within the MET enhancer suppressed inducible chromatin looping and innate drug resistance, while maintaining MITF-dependent, inhibitor-induced melanoma cell differentiation. Epigenomic analysis can thus guide functional disruption of regulatory DNA to decouple pro- and anti-oncogenic functions of tumor lineage-enriched transcription factors mediating innate resistance to oncokinase therapy. MITF ChIP-seq was performed in primary human melanocytes with overexpression of BRAFV600E or a lentiviral control (RFP), and in COLO829 melanoma cells treated with DMSO, or PLX4032

2014-01-14 | E-GEOD-50681 | biostudies-arrayexpress

Genome-wide reprogramming of the chromatin landscape underlies endocrine therapy resistance in breast cancer

Project description:The estrogen receptor alpha (ERa) drives the growth of two-thirds of all breast cancers. Endocrine therapy impinges on estrogen-induced ERa activation to block tumor growth. However, half of ERa-positive breast cancers are tolerant or acquire endocrine therapy resistance. Here we demonstrate that breast cancer cells undergo genome-wide reprogramming of their chromatin landscape, defined by epigenomic maps and chromatin openness, as they acquire resistance to endocrine therapy. This reveals a role for the Notch pathway while excluding classical ERa signaling. In agreement, blocking Notch signaling, using gamma-secretase inhibitors, or targeting its downstream gene PBX1 abrogates growth of endocrine therapy-resistant breast cancer cells. Moreover Notch signaling through PBX1 directs a transcriptional program predictive of tumor outcome and endocrine therapy response. Comparing histone modifications (H3K4me2 and H3K36me3), chromatin openness (FAIRE) and PBX1 binding between endocrine therapy sensitive MCF7 and resistant MCF7-LTED cells.

2013-05-01 | E-GEOD-37323 | biostudies-arrayexpress

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