Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA394838 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:JMJD6 licenses estrogen receptor alpha-dependent enhancer RNA and coding gene activation by modulating CARM1/MED12 co-activator complex in breast cancer
| PRJNA394829 | ENA
Project description:JMJD6 licenses estrogen receptor alpha-dependent enhancer RNA and coding gene activation by modulating CARM1/MED12 co-activator complex in breast cancer [ChIP-Seq]
| PRJNA394837 | ENA
Project description:Enhancers are genomic regulatory elements shown to play key roles in controlling cell type-specific gene expression, regulated by signal-dependent transcription factors and co-factors. Distinct classes of enhancers can specify distinct gene expression profiles and biological outcomes. Recent studies suggested that bidirectional non-coding RNAs (ncRNAs), referred as enhancer RNA (eRNAs), are transcribed on enhancers, which are tightly associated with enhancer activity. However, the protein factors which govern the activation of enhancers remain poorly characterized. Here we reported that a Jumonji C (JmjC) domain-containing protein demethylase, JMJD6, is a determinant for estrogen/estrogen receptor (ER)-induced enhancer activation, coding gene transcription, breast cancer cell growth and tumorigenesis. Mechanistically, JMJD6 was found to be specifically recruited onto ER-bound active enhancers in response to estrogen stimulation, which was required for RNA Pol II recruitment and eRNA production of enhancers, leading to transcriptional activation of cognate estrogen target genes. Furthermore, JMJD6 was found to be physically and functionally associated with MED12 in the mediator complex to regulate estrogen-induced transcriptional activation, with JMJD6 was required for MED12 recruitment onto active enhancers. Specifically, JMJD6 was essential for MED12 to interact with CARM1, an arginine methyltransferase well known to be implicated in estrogen-induced transcriptional activation, which methylated MED12 at its c-terminus at multiple arginine methylation sites and was required for MED12 binding with chromatin. Collectively, our data uncovered a critical regulator of estrogen/estrogen receptor-induced enhancer activation and coding gene transcription, providing a potential drug candidate for developing novel strategies targeting ER-positive breast cancers.
2018-04-16 | GSE101560 | GEO
Project description:Enhancers are genomic regulatory elements shown to play key roles in controlling cell type-specific gene expression, regulated by signal-dependent transcription factors and co-factors. Distinct classes of enhancers can specify distinct gene expression profiles and biological outcomes. Recent studies suggested that bidirectional non-coding RNAs (ncRNAs), referred as enhancer RNA (eRNAs), are transcribed on enhancers, which are tightly associated with enhancer activity. However, the protein factors which govern the activation of enhancers remain poorly characterized. Here we reported that a Jumonji C (JmjC) domain-containing protein demethylase, JMJD6, is a determinant for estrogen/estrogen receptor (ER)-induced enhancer activation, coding gene transcription, breast cancer cell growth and tumorigenesis. Mechanistically, JMJD6 was found to be specifically recruited onto ER-bound active enhancers in response to estrogen stimulation, which was required for RNA Pol II recruitment and eRNA production of enhancers, leading to transcriptional activation of cognate estrogen target genes. Furthermore, JMJD6 was found to be physically and functionally associated with MED12 in the mediator complex to regulate estrogen-induced transcriptional activation, with JMJD6 was required for MED12 recruitment onto active enhancers. Specifically, JMJD6 was essential for MED12 to interact with CARM1, an arginine methyltransferase well known to be implicated in estrogen-induced transcriptional activation, which methylated MED12 at its c-terminus at multiple arginine methylation sites and was required for MED12 binding with chromatin. Collectively, our data uncovered a critical regulator of estrogen/estrogen receptor-induced enhancer activation and coding gene transcription, providing a potential drug candidate for developing novel strategies targeting ER-positive breast cancers.
2018-04-16 | GSE101559 | GEO
Project description:The coactivator-associated arginine methyltransferase (CARM1) functions as a regulator for transcription, splicing and chromatin regulation by methylating a diverse array of substrates. In this study, we used CARM1 substrate antibodies to perform immunoprecipitation coupled with mass spectrometry (IP-MS) in MEFs and identified Mediator Subunit 12 (MED12) as a novel substrate for CARM1. ChIP-seq analysis using CARM1, MED12 and H3R17me2a (represents ‘CARM1 activity’) antibodies revealed that MED12 targeted by CARM1 is recruited to the EREs (estrogen-responsive elements). Additionally, RT-PCR studies showed that the MED12R1899K mutation disrupting the methylation site reduced the expression of ER-target genes. Thus, MED12 methylation targets it to ER-specific enhancers and positively modulates transcription of Estrogen-driven genes.
2018-09-05 | GSE72848 | GEO
Project description:While protein arginine methyltransferases (PRMTs) and PRMT-catalyzed protein methylation have been well-known to be involved in a myriad of biological processes, their roles in carcinogenesis, particularly in estrogen receptor alpha (ERa)-positive breast cancers, remain incompletely understood. Here we focused on investigating PRMT4 (also called coactivator associated arginine methyltransferase 1, CARM1) due to its high expression and the associated poor prognosis in ERa-positive breast cancers. We first uncovered the chromatin-binding landscape and transcriptional targets of CARM1 in the presence of estrogen in ERa-positive breast cancer cells employing genomic and transcriptomics approaches. CARM1 was found to be predominantly and specifically recruited to ERa-bound active enhancers and essential for the transcriptional activation of cognate estrogen-induced gene transcriptional activation in response to estrogen. Global mapping of CARM1 substrates revealed that CARM1 methylates a large cohort of proteins with diverse biological functions, including regulation of intracellular estrogen receptor signaling, chromatin organization, chromatin remodeling and others. Intriguingly, a number of proteins were hypermethylated exclusively by CARM1 on a cluster of arginine residues. Exemplified by MED12, hypermethylation of these proteins by CARM1 served as a molecular beacon for recruiting coactivator protein, tudor domain-containing 3 (TDRD3), to ensure the full activation of estrogen/ERa target genes. In consistent with its critical role in estrogen-induced gene transcriptional activation, CARM1 was found to promote cell proliferation of ERa-positive breast cancer cells in vitro and tumor growth in mice. Taken together, our study uncovered a “hypermethylation” strategy utilized by CARM1 in gene transcriptional regulation, and suggested that CARM1 can server as a therapeutic target for breast cancer treatment.
2020-01-17 | GSE124447 | GEO
Project description:While protein arginine methyltransferases (PRMTs) and PRMT-catalyzed protein methylation have been well-known to be involved in a myriad of biological processes, their roles in carcinogenesis, particularly in estrogen receptor alpha (ERa)-positive breast cancers, remain incompletely understood. Here we focused on investigating PRMT4 (also called coactivator associated arginine methyltransferase 1, CARM1) due to its high expression and the associated poor prognosis in ERa-positive breast cancers. We first uncovered the chromatin-binding landscape and transcriptional targets of CARM1 in the presence of estrogen in ERa-positive breast cancer cells employing genomic and transcriptomics approaches. CARM1 was found to be predominantly and specifically recruited to ERa-bound active enhancers and essential for the transcriptional activation of cognate estrogen-induced gene transcriptional activation in response to estrogen. Global mapping of CARM1 substrates revealed that CARM1 methylates a large cohort of proteins with diverse biological functions, including regulation of intracellular estrogen receptor signaling, chromatin organization, chromatin remodeling and others. Intriguingly, a number of proteins were hypermethylated exclusively by CARM1 on a cluster of arginine residues. Exemplified by MED12, hypermethylation of these proteins by CARM1 served as a molecular beacon for recruiting coactivator protein, tudor domain-containing 3 (TDRD3), to ensure the full activation of estrogen/ERa target genes. In consistent with its critical role in estrogen-induced gene transcriptional activation, CARM1 was found to promote cell proliferation of ERa-positive breast cancer cells in vitro and tumor growth in mice. Taken together, our study uncovered a “hypermethylation” strategy utilized by CARM1 in gene transcriptional regulation, and suggested that CARM1 can server as a therapeutic target for breast cancer treatment.
2020-03-31 | GSE124448 | GEO
Project description:Several cancer drugs activate innate immune pathways in tumor cells but unfortunately compromise anti-tumor immune function. We discovered that inhibition of Carm1, an epigenetic enzyme, elicited beneficial effects in both cytotoxic T cells and tumor cells. Carm1 inactivation in cytotoxic T cells enhanced their activation state and anti-tumor function. In contrast, Carm1 inhibition in tumor cells resulted in genomic damage and activation of the cGAS-STING pathway. Inactivation of Med12, a regulatory component of the Mediator complex, elicited the same tumor cell phenotype, thereby connecting Carm1 to regulation of transcription. Inhibition of Carm1 induced potent T cell mediated tumor immunity and sensitized resistant, highly aggressive tumor cells to checkpoint blockade. The Carm1 – Med12 pathway thus offers an opportunity to enhance anti-tumor immunity while simultaneously sensitizing resistant tumor cells to immune attack.
2022-01-31 | GSE144917 | GEO
Project description:Coactivator associated arginine methyltransferase 1 has been reported to play paramount roles in estrogen receptor alpha (ERα)-positive breast cancer. It promotes breast cancer development and metastasis. However, little research about CARM1 has been focused on triple-negative breast cancer (TNBC). Here, we report that CARM1 promotes proliferation, epithelial-mesenchymal transition (EMT) and stemness in TNBC. CARM1 transactivates Hypoxia-inducible factor 1 subunit alpha (HIF1A) and is physically associated with it. They function together in a concerted complex to regulate downstream targets and promote the carcinogenesis and metastasis of TNBC.
2024-02-24 | GSE167394 | 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