JMJD6 licenses estrogen receptor alpha-dependent enhancer RNA and coding gene activation by modulating CARM1/MED12 co-activator complex in breast cancer
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ABSTRACT:
PROVIDER: PRJNA394829 | ENA |
REPOSITORIES: ENA
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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: Not available
| S-EPMC6258263 | biostudies-literature
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:This SuperSeries is composed of the SubSeries listed below.
2018-04-16 | GSE101562 | GEO
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:JMJD6 licenses estrogen receptor alpha-dependent enhancer RNA and coding gene activation by modulating CARM1/MED12 co-activator complex in breast cancer [Gro-Seq]
| PRJNA394838 | ENA
Project description:The Jumonji domaining-containing protein JMJD6 is a 2-oxoglutarate dependent dioxygenase that has been implicated in a broad range of biological functions. Cellular studies have implicated the enzyme in chromatin biology, transcription, DNA repair, mRNA splicing and co-transcriptional processing. Although not all studies agree, JMJD6 has been reported to catalyse both hydroxylation of lysine residues and demethylation of arginine residues. However, despite extensive study and the indirect implication of JMJD6 catalysis in many cellular processes, direct assignment of JMJD6 catalytic substrates has been limited. Examination of a site of reported prolyl hydroxylation within a lysine-rich region of the bromodomain protein BRD4 led us to conclude that hydroxylation was in fact on lysine and catalysed by Jmjd6. This prompted a wider search for JMJD6-catalysed protein modifications deploying mass spectrometric methods designed to identify novel substrate associations and facilitate analysis of lysine-rich regions by LC-MSMS. Using derivatization of lysine with propionic anhydride to improve the analysis of tryptic peptides and a pharmacological inhibitor of JMJD6 to stabilise enzyme/substrate associations, we report over 100 sites of JMJD6-catalysed lysyl hydroxylation on 48 protein substrates including 19 sites of hydroxylation on BRD4. Most hydroxylations were within lysine-rich regions that are predicted to be unstructured; in some multiple modifications were observed on adjacent lysine residues. Almost all of the JMJD6 substrates defined in this study have been associated with membraneless organelle formation. Taken together with findings implicating lysine-rich regions in subcellular partitioning by liquid-liquid phase separation, our findings raise the possibility that JMJD6 may play a role in regulating such processes in response to stresses, including hypoxia. Note, this dataset corresponds to Figure 3 of the published manuscript; which employs a substrate-trapping methodology to identify novel substrates of JMJD6 by label free DIA approach.
2022-08-02 | PXD031155 | Pride
Project description:The goal of the project was global identification of CARM1 substrates. Arginine methylation landscapes were profiled and compared in wild type and CARM1 knockout cells to determine in vivo substrates of CARM1.
2017-07-03 | PXD005871 | Pride