Target Gene Repression Based on Dismissal of Polymerase II from Estrogen Receptor Trans-bound Enhancers Is Associated With Clinical Outcome in Human Breast Cancer [ChIP-seq]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE73956 | GEO | 2019/09/04
REPOSITORIES: GEO
Similar Datasets
Project description:We find that 17-β-estradiol (E2)-bound estrogen receptor α (ERα) is bound in trans to a cohort of FOXA1-dependent, constitutively activate enhancers, inactivating these enhancers by decommissioning/removing enhancer Polymerase II (Pol II), despite recruitment of coactivators. This is based on the surprising recruitment by the ERα DNA binding domain of the histone demethylase, KDM2A, which, functioning independently of its demethylase function. KDM2A mediates recruitment of NEDD4 complexes that ubiquitinate and dismisses Pol II from these "repressive" enhancers, resulting in the E2 down-regulated transcriptional program.
2019-09-04 | GSE73957 | GEO
Project description:Estrogen receptor alpha (ERα) signaling mainly occupies on distal enhancers within genome and plays an essential role in ERα-positive breast cancer. ERα usually requires co-factors to regulate the enhancer activity. By analysis of genome-wide nascent transcript profiling in breast cancer cells, we identified a special group of eRNAs that are functionally important for estrogen-induced transcriptional repression. In addition to stabilizing promoter-enhancer looping structure, these eRNAs recruit ERα to particular enhancers of target genes, facilitate the hierarchical formation of a functional transcriptional complex, and cause gene silencing. Interestingly, we found that ERα directly binds to eRNAs and its DNA-binding domain mediates the interaction with RNA molecules. Our ChIP-seq data in MCF-7 cells indicating that ERαwas not able to bind to E2-activated enhancers, which is consistent with the DNA-binding function reported before; moreover the DBD-truncated ERα was not able to bind to E2-repressed enhancers as well, which further supports our hypothesis that eRNA from E2-repressed enhancers help to recruit ERα to specific enhancers through the interaction with DBD domain. Substitution of ERα-DDBD showed a global effect on both induction and repression of ERα target genes as examined by RNA-seq. Further, these eRNAs help with the formation of a specific ERα-centered transcriptional complex and promote the association of the histone demethylase KDM2A, which dismisses RNA polymerase II from designated enhancers and suppresses transcription of target genes. Our work demonstrated that eRNAs, as a distinctive class of cis-acting molecules besides chromatin regulatory elements, play an important role in modulating and refining locus-specific transcriptional program.
2020-06-23 | GSE135340 | GEO
Project description:Estrogen receptor alpha (ERα) signaling mainly occupies on distal enhancers within genome and plays an essential role in ERα-positive breast cancer. ERα usually requires co-factors to regulate the enhancer activity. By analysis of genome-wide nascent transcript profiling in breast cancer cells, we identified a special group of eRNAs that are functionally important for estrogen-induced transcriptional repression. In addition to stabilizing promoter-enhancer looping structure, these eRNAs recruit ERα to particular enhancers of target genes, facilitate the hierarchical formation of a functional transcriptional complex, and cause gene silencing. Interestingly, we found that ERα directly binds to eRNAs and its DNA-binding domain mediates the interaction with RNA molecules. Our ChIP-seq data in MCF-7 cells indicating that ERαwas not able to bind to E2-activated enhancers, which is consistent with the DNA-binding function reported before; moreover the DBD-truncated ERα was not able to bind to E2-repressed enhancers as well, which further supports our hypothesis that eRNA from E2-repressed enhancers help to recruit ERα to specific enhancers through the interaction with DBD domain. Substitution of ERα-DDBD showed a global effect on both induction and repression of ERα target genes as examined by RNA-seq. Further, these eRNAs help with the formation of a specific ERα-centered transcriptional complex and promote the association of the histone demethylase KDM2A, which dismisses RNA polymerase II from designated enhancers and suppresses transcription of target genes. Our work demonstrated that eRNAs, as a distinctive class of cis-acting molecules besides chromatin regulatory elements, play an important role in modulating and refining locus-specific transcriptional program.
2020-06-23 | GSE135339 | GEO
Project description:Gene regulatory programs in different cell types are largely defined through cell-specific enhancers activity. The histone variant H2A.Z has been shown to play important roles in transcription mainly by controlling proximal promoters, but its effect on enhancer functions remains unclear. Here, we demonstrate by genome-wide approaches that H2A.Z is present at a subset of active enhancers bound by the estrogen receptor alpha (ERα). We also determine that H2A.Z does not influence the local nucleosome positioning around ERα-enhancers using ChIP-sequencing at nucleosomal resolution and unsupervised pattern discovery. We further highlight that H2A.Z-enriched enhancers are associated with chromatin accessibility, H3K122ac enrichment and hypomethylated DNA. Moreover, upon estrogen stimulation, the enhancers occupied by H2A.Z produce enhancer RNAs (eRNAs), and recruit RNA polymerase II as well as RAD21, a member of the cohesin complex involved in chromatin interactions between enhancers and promoters. Importantly, their recruitment and eRNAs production are abolished by H2A.Z depletion, thereby revealing a novel functional link between H2A.Z occupancy and enhancer activity. Taken together, our findings suggest that H2A.Z acts as an important player for enhancer functions by establishing and maintaining a chromatin environment required for RNA polymerase II recruitment, eRNAs transcription and enhancer-promoters interactions, all essential attributes of enhancer activity. The MNase ChIP-seqs in this study measure the genome-wide binding landscape of H2A.Z, H3K4me1, H3K27ac and H3K4me3 in MCF-7 cells in the absence or presence of E2. Two biological replicates were done for each ChIP-seq experiment and for each condition, as well as, control input.
2015-08-31 | E-GEOD-57436 | biostudies-arrayexpress
Project description:SET is a multifunctional histone-binding oncoprotein that regulates transcription by an unclear mechanism. Here, we show that SET enhances estrogen-dependent transcription. SET knockdown abrogates transcription of estrogen-responsive genes and their enhancer RNAs (eRNAs). In response to 17β-estradiol (E2), SET binds to the estrogen receptor α (ERα) and is recruited to estrogen receptor α (ERα)-bound enhancers and promoters at estrogen response elements (EREs). SET functions as a histone H2 chaperone that dynamically associates with H2A.Z via its acidic C-terminal domain and promotes H2A.Z incorporation, ERα, MLL1 and KDM3A loading and modulates histone methylation at EREs. SET depletion diminishes recruitment of condensin complexes to EREs and impairs E2-dependent enhancer-promoter looping. Thus, SET boosts E2-induced gene expression by establishing an active chromatin structure at ERα-bound enhancers and promoters, which is essential for transcriptional activation.
2023-02-02 | GSE218815 | GEO
Project description:SET is a multifunctional histone-binding oncoprotein that regulates transcription by an unclear mechanism. Here, we show that SET enhances estrogen-dependent transcription. SET knockdown abrogates transcription of estrogen-responsive genes and their enhancer RNAs (eRNAs). In response to 17β-estradiol (E2), SET binds to the estrogen receptor α (ERα) and is recruited to estrogen receptor α (ERα)-bound enhancers and promoters at estrogen response elements (EREs). SET functions as a histone H2 chaperone that dynamically associates with H2A.Z via its acidic C-terminal domain and promotes H2A.Z incorporation, ERα, MLL1 and KDM3A loading and modulates histone methylation at EREs. SET depletion diminishes recruitment of condensin complexes to EREs and impairs E2-dependent enhancer-promoter looping. Thus, SET boosts E2-induced gene expression by establishing an active chromatin structure at ERα-bound enhancers and promoters, which is essential for transcriptional activation.
2023-02-01 | GSE200900 | GEO
Project description:Estrogen and estrogen receptor alpha (ERα) signaling plays an essential role in ERα-positive breast cancer. ERα mainly occupies on distal enhancers within genome and requires the cooperation of additional co-factors to tune the enhancer activity. Through in vivo proximity-dependent labeling technique BioID, we identified YAP1 and TEAD4 protein as novel co-regulators of ERα. YAP and TEAD are nuclear effectors of the Hippo pathway regulating cell proliferation, organ size and tumorigenesis. Their non-canonical function as transcriptional co-regulators for other signals have been reported but remains under investigated. Our ChIP-seq data in both MCF7 and T47D breast cancer cell lines indicated that YAP1 and TEAD4 co-bind to the strongest estrogen-responsive ERα-bound enhancers, and their bindings are augmented upon E2 stimulation. Knockdown of YAP1 or TEAD4 showed a global effect on the induction of E2/ERα target genes as examined by RNA-seq, also on E2-induced oncogenic growth of ER-positive breast cancer cells. We used Global Run-on sequencing (GRO-seq) assays to test the expression of enhancer non-coding RNAs (eRNAs), which are sensitive markers for estrogen-induced enhancer activation. Our results supported our hypothesis that the recruitment YAP/TEAD to ERα-bound enhancers is required for enhancer activation. Further studies revealed that the binding of YAP1 on ERα enhancers is a prerequisite for the recruitment of the enhancer activation machinery component MED1. These findings indicate that ERα collaborates with YAP1 and TEAD4 to activate or maintain its enhancer activity. Our data reveals a non-canonical function of YAP1 and TEAD4, which is independent of their canonical target genes, in regulating cancer growth, highlighting the potential of YAP1 and TEAD4 as actionable drug targets for ERα-positive breast cancer.
2019-07-16 | GSE125594 | GEO
Project description:Estrogen and estrogen receptor alpha (ERα) signaling plays an essential role in ERα-positive breast cancer. ERα mainly occupies on distal enhancers within genome and requires the cooperation of additional co-factors to tune the enhancer activity. Through in vivo proximity-dependent labeling technique BioID, we identified YAP1 and TEAD4 protein as novel co-regulators of ERα. YAP and TEAD are nuclear effectors of the Hippo pathway regulating cell proliferation, organ size and tumorigenesis. Their non-canonical function as transcriptional co-regulators for other signals have been reported but remains under investigated. Our ChIP-seq data in both MCF7 and T47D breast cancer cell lines indicated that YAP1 and TEAD4 co-bind to the strongest estrogen-responsive ERα-bound enhancers, and their bindings are augmented upon E2 stimulation. Knockdown of YAP1 or TEAD4 showed a global effect on the induction of E2/ERα target genes as examined by RNA-seq, also on E2-induced oncogenic growth of ER-positive breast cancer cells. We used Global Run-on sequencing (GRO-seq) assays to test the expression of enhancer non-coding RNAs (eRNAs), which are sensitive markers for estrogen-induced enhancer activation. Our results supported our hypothesis that the recruitment YAP/TEAD to ERα-bound enhancers is required for enhancer activation. Further studies revealed that the binding of YAP1 on ERα enhancers is a prerequisite for the recruitment of the enhancer activation machinery component MED1. These findings indicate that ERα collaborates with YAP1 and TEAD4 to activate or maintain its enhancer activity. Our data reveals a non-canonical function of YAP1 and TEAD4, which is independent of their canonical target genes, in regulating cancer growth, highlighting the potential of YAP1 and TEAD4 as actionable drug targets for ERα-positive breast cancer.
2019-07-16 | GSE125606 | GEO
Project description:Estrogen and estrogen receptor alpha (ERα) signaling plays an essential role in ERα-positive breast cancer. ERα mainly occupies on distal enhancers within genome and requires the cooperation of additional co-factors to tune the enhancer activity. Through in vivo proximity-dependent labeling technique BioID, we identified YAP1 and TEAD4 protein as novel co-regulators of ERα. YAP and TEAD are nuclear effectors of the Hippo pathway regulating cell proliferation, organ size and tumorigenesis. Their non-canonical function as transcriptional co-regulators for other signals have been reported but remains under investigated. Our ChIP-seq data in both MCF7 and T47D breast cancer cell lines indicated that YAP1 and TEAD4 co-bind to the strongest estrogen-responsive ERα-bound enhancers, and their bindings are augmented upon E2 stimulation. Knockdown of YAP1 or TEAD4 showed a global effect on the induction of E2/ERα target genes as examined by RNA-seq, also on E2-induced oncogenic growth of ER-positive breast cancer cells. We used Global Run-on sequencing (GRO-seq) assays to test the expression of enhancer non-coding RNAs (eRNAs), which are sensitive markers for estrogen-induced enhancer activation. Our results supported our hypothesis that the recruitment YAP/TEAD to ERα-bound enhancers is required for enhancer activation. Further studies revealed that the binding of YAP1 on ERα enhancers is a prerequisite for the recruitment of the enhancer activation machinery component MED1. These findings indicate that ERα collaborates with YAP1 and TEAD4 to activate or maintain its enhancer activity. Our data reveals a non-canonical function of YAP1 and TEAD4, which is independent of their canonical target genes, in regulating cancer growth, highlighting the potential of YAP1 and TEAD4 as actionable drug targets for ERα-positive breast cancer.
2019-07-16 | GSE125607 | GEO
Project description:Distal enhancers characterized by H3K4me1 mark play critical roles in developmental and transcriptional programs. However, potential roles of specific distal regulatory elements in regulating RNA Polymerase II (Pol II) promoter-proximal pause release remain poorly investigated. Here we report that a unique cohort of jumonji C domain-containing protein 6 (JMJD6) and bromodomain-containing protein 4 (Brd4) co-bound distal enhancers, termed anti-pause enhancers (A-PEs), regulate promoter-proximal pause release of a large subset of transcription units via long-range interactions. Brd4-dependent JMJD6 recruitment on A-PEs mediates erasure of H4R3me2(s), which is directly read by 7SK snRNA, and decapping/demethylation of 7SK snRNA, ensuring the dismissal of the 7SKsnRNA/HEXIM inhibitory complex. The interactions of both JMJD6 and Brd4 with the P-TEFb complex permit its activation and pause release of regulated coding genes. The functions of JMJD6/ Brd4-associated dual histone and RNA demethylase activity on anti-pause enhancers have intriguing implications for these proteins in development, homeostasis and disease. All Gro-seq(s) were designed to reveal the transcriptional targets of JMJD6 and Brd4, and assess the role of JMJD6 and Brd4 in Pol II promoter-proximal pause release. All ChIP-seq(s) were designed to understand the unique features, associated molecular mechanisms and functions of the anti-pause enhancers (A-PEs) discovered in the current study.
2014-01-14 | E-GEOD-51633 | biostudies-arrayexpress