MED12
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ABSTRACT:
PROVIDER: PRJEB25198 | ENA |
REPOSITORIES: ENA
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Project description:MED12 is an X-chromosome member of the Mediator complex that is a key regulator of tissue specific gene expression and moderates intracellular signaling via multiple developmental pathways. Sequence variations in the carboxy-terminus of MED12, which contains a PQL and Opa domain, are associated with X-linked mental retardation behavioral syndromes and schizophrenia. Unfortunately, the mechanism(s) through which MED12 sequence variation in the carboxy-terminus could alter vulnerability to neurodevelomental and neuropsychiatric illnesses is yet unclear. In order to elucidate a better understanding of this process, we examined the role of the MED12 carboxy-terminus in cell cycle and gene expression with full-length and domain deleted overexpression constructs and RNA interference in HEK293 cells. Our microarray data show a set of genes differentially expressed in the experimental conditions versus the GFP control. The top 50 most differentially expressed genes in the experimental conditions versus the GFP control also show that MED12 expression level differentially affects stress response and transcriptional regulation pathways. These results are consistent with prior studies showing that MED12 has a key role in determining neuronal cell fate and our theoretical understanding of the biological basis of psychosis. They also lend further insight upon the pathways through which MED12 exerts its effects upon differentiation and disease pathogenesis, which may one day lead to new approaches to the treatment of MED12-related disorders. 12 samples were analyzed, being comprised of four conditions with three biological replicates. Comparisons were made between the GFP control to experimental condition (i.e. GFP vs MED12 FL; GFP vs MED12 PQL/Opa; and GFP vs MED12 shRNA 5)
2011-08-10 | E-GEOD-31327 | biostudies-arrayexpress
Project description:MED12 is an X-chromosome member of the Mediator complex that is a key regulator of tissue specific gene expression and moderates intracellular signaling via multiple developmental pathways. Sequence variations in the carboxy-terminus of MED12, which contains a PQL and Opa domain, are associated with X-linked mental retardation behavioral syndromes and schizophrenia. Unfortunately, the mechanism(s) through which MED12 sequence variation in the carboxy-terminus could alter vulnerability to neurodevelomental and neuropsychiatric illnesses is yet unclear. In order to elucidate a better understanding of this process, we examined the role of the MED12 carboxy-terminus in cell cycle and gene expression with full-length and domain deleted overexpression constructs and RNA interference in HEK293 cells. Our microarray data show a set of genes differentially expressed in the experimental conditions versus the GFP control. The top 50 most differentially expressed genes in the experimental conditions versus the GFP control also show that MED12 expression level differentially affects stress response and transcriptional regulation pathways. These results are consistent with prior studies showing that MED12 has a key role in determining neuronal cell fate and our theoretical understanding of the biological basis of psychosis. They also lend further insight upon the pathways through which MED12 exerts its effects upon differentiation and disease pathogenesis, which may one day lead to new approaches to the treatment of MED12-related disorders.
2011-08-11 | GSE31327 | GEO
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
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 | GSE204969 | GEO
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
Project description:The RNA polymerase II transcriptional Mediator subunit MED12 is broadly implicated in vertebrate brain development, and genetic variation in human MED12 is associated with X-linked intellectual disability and neuropsychiatric disorders. Although prior studies have begun to elaborate the functional contribution of MED12 within key neurodevelopmental pathways, a more complete description of MED12 function in the developing nervous system, including the specific biological networks and cellular processes under its regulatory influence, remains to be established. Herein, we sought to clarify the global contribution of MED12 to neural stem cell (NSC) biology through unbiased transcriptome profiling of mouse embryonic stem (ES) cell-derived NSCs following RNAi-mediated MED12 depletion. A total of 240 genes (177 up, 73 down) were differentially expressed in MED12-knockdown versus control mouse NS-5 (mNS-5) NSCs. Gene set enrichment analysis revealed MED12 to be prominently linked with “cell-to-cell interaction” and “cell cycle” networks, and subsequent functional studies confirmed these associations. Targeted depletion of MED12 led to enhanced NSC adhesion and upregulation of cell adhesion genes, including Syndecan 2 (SDC2). Concomitant depletion of both SDC2 and MED12 reversed enhanced cell adhesion triggered by MED12 knockdown alone, confirming that MED12 negatively regulates NSC cell adhesion by suppressing the expression of cell adhesion molecules. MED12-mediated suppression of NSC adhesion is a dynamically regulated process in vitro, enforced in self-renewing NSCs and alleviated during the course of neuronal differentiation. Accordingly, MED12 depletion enhanced adhesion and prolonged survival of mNS-5 NSCs induced to differentiate on gelatin, effects that were bypassed completely by growth on laminin. On the other hand, MED12 depletion in mNS-5 NSCs led to reduced expression of G1/S phase cell cycle regulators and a concordant G1/S phase cell cycle block without evidence of apoptosis, resulting in a severe proliferation defect. These findings suggest that MED12 contributes to the maintenance of NSC identity through a functionally bipartite role in suppression and activation of gene expression programs dedicated to cell adhesion and G1/S phase cell cycle progression, respectively. MED12 may thus contribute to the regulatory apparatus that controls the balance between NSC self-renewal and differentiation, with important implications for MED12-linked neurodevelopmental disorders.
2016-05-19 | GSE80624 | GEO
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
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 | GSE242080 | GEO
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 | GSE242096 | GEO
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 | GSE242083 | GEO