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Marker-based CRISPR screening reveals a direct MED12-p63 interaction that activates basal identity in pancreatic ductal adenocarcinoma

ABSTRACT: We report a novel p63-MED12 transcriptional complex that is selectively required for basal pancreatic cancer and squamous cell carcinoma survival. This transcription factor-imposed genetic vulnerability on a general coactivator will inform future p63-blocking therapeutic strategies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE229062 | GEO | 2023/12/06

REPOSITORIES: GEO

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Marker-based CRISPR screening reveals a direct MED12-p63 interaction that activates basal identity in pancreatic ductal adenocarcinoma

Project description:Marker-based CRISPR screening reveals a direct MED12-p63 interaction that activates basal identity in pancreatic ductal adenocarcinoma

| PRJNA952663 | ENA

CARM1 Methylates MED12 to Regulate its RNA Binding Ability

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

MED12 mutation activates the tryptophan/kynurenine/AHR pathway to promote growth of uterine leiomyomas

Project description:Uterine leiomyoma (LM) is the most common tumor in women. Estrogen and progesterone, via their receptors ERα and PR, play essential roles in LM growth. Mediator complex subunit 12 (MED12) mutations occur in 70% of all LM and are thought to drive tumor growth in a steroid hormone-dependent manner; however, the mechanisms remain unclear. Here, we performed ChIP-seq (ERα, PR, and MED12) and RNA-seq on LM expressing mutant MED12 (mut-MED12) or wild-type MED12 and matched myometrium. Mut-MED12 altered PR and chromatin interaction landscapes, with significant PR-binding site loss in proximal promoter regions in mut-MED12 LM. Integration of cistrome and transcriptome data identified tryptophan 2,3-dioxygenase (TDO2) as a PR and MED12 target gene, which was aberrantly upregulated in mut-MED12 LM. Kynurenine, the catabolic product of TDO2, was significantly elevated in mut-MED12 LM. Tryptophan or kynurenine treatment of primary LM cells activated the aryl hydrocarbon receptor (AHR) pathway, increased cell proliferation, and inhibited apoptosis; blocking the TDO2-kynurenine-AHR pathway by siRNA knockdown or pharmacologic inhibition abolished these effects. Mut-MED12 LM cells showed higher sensitivity to these treatments. These findings suggest that activation of the TDO2-kynurenine-AHR pathway in mut-MED12 LM induces tumor growth, and may inform the development of targeted treatments and precision medicine in LM.

2023-05-01 | GSE204968 | GEO

Identification of p63 binding regions in a p63 expressing basal-subtype breast cancer cell line, MCFDCIS.

Project description:p63 ChIP-SEQ in a p63 expressing basal-subtype breast cancer cell line, MCFDCIS and in a p63 deficient claudin-low subtype breast cancer cell line, MDA-MB-231 p63 ChIP-SEQ on MCFDCIS and MDA-MB-231 cell lines

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Identification of p63 binding regions in a p63 expressing basal-subtype breast cancer cell line, MCFDCIS.

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Determination of MED12 protein interactome

Project description:Here, the goal of our study was to determine the protein-protein interactome of MED12 in resting and activated human T-cells. We immunoprecipitated endogenous MED12 and evaluated the protein interactome in comparison to an isotype-matched IgG as a control.

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Med12 ablation promotes anti-tumor function by enhancing tumor intrinsic immunogenicity in Pancreatic ductal adenocarcinoma [CUT&Tag]

Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with limited treatment options, including checkpoint blockade (ICB) immunotherapy. Epigenetic dysregulation is a defining feature of tumorigenesis and contributes to immune escape. However, little is known about whether and how epigenetic regulators evade immune surveillance in PDAC. Here, we identified Med12, a subunit of RNA polymerase II, as a mediator of immune escape in PDAC with in vivo CRISPR-Cas9 Screening. In murine PDAC models, Med12 loss effectively promoted infiltration and cytotoxicity of CD8+ T cells and NK cells，thereby sensitized to ICB and led to a marked extension of survival. Mechanistically, Med12 loss derepressed endogenous retroelements via impairing H3K9me3 and increasing H3K27Ac modification, triggering cytosolic RNA-sensing and DNA-sensing pathways as well as the type I interferon pathways. Moreover, Med12 depletion induced H3K27Ac gain in the Med12-binding domains, further enhanced the interferon-related genes transcription. Our results demonstrated the role of Med12 in suppressing tumor-intrinsic immunogenicity, thus provided a potential target or marker for immunotherapy of PDAC.

2023-11-30 | GSE242097 | GEO

Med12 ablation promotes anti-tumor function by enhancing tumor intrinsic immunogenicity in Pancreatic ductal adenocarcinoma [ATAC-seq]

2023-11-30 | GSE242080 | GEO

Med12 and p300 chips in HSPCs

Project description:We characterized the genome wide occupancy of Med12 and p300 in mouse HSPCs. We also characterize p300 occupancy upon shRNA against control or Med12. ChIP-seq analysis of Med12 and/or p300 in untreated HSPCs

2016-08-25 | E-GEOD-76053 | biostudies-arrayexpress

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