The Role of Mediator Subunit MED30 in Licensing the c-Myc Oncogenic Program
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ABSTRACT:
PROVIDER: PRJNA1047600 | ENA |
REPOSITORIES: ENA
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Project description:Despite extensive functional and structural investigation of the Mediator complex, the basis for selective functional requirements for specific Mediator subunits for the actions of specific DNA binding transcription factors remain incompletely understood. Here, we report the MED30 subunit of Mediator, one of the core subunits maintaining the complex, plays a critical role in regulating the MYC transcription program in cancer cells. This is consequent to MED30 being required for stabilizing Mediator complex and MYC binding on the genome, involving low-affinity hydrophobic interaction functions of the MYC N-terminal Intrinsic Disordered Region (IDR). A mutational screen reveals that mutations in critical residues in the MYC coiled-coil domain structurally adjacent to the IDR of MED30 strongly inhibit tumor growth, even in the presence of wild-type MED30, mimicking the effects of MED30 deletion. This study provides new insights into the principles governing the Mediator complex actions MYC-related biological processes.
2024-11-24 | GSE249177 | GEO
Project description:Despite extensive functional and structural investigation of the Mediator complex, the basis for selective functional requirements for specific Mediator subunits for the actions of specific DNA binding transcription factors remain incompletely understood. Here, we report the MED30 subunit of Mediator, one of the core subunits maintaining the complex, plays a critical role in regulating the MYC transcription program in cancer cells. This is consequent to MED30 being required for stabilizing Mediator complex and MYC binding on the genome, involving low-affinity hydrophobic interaction functions of the MYC N-terminal Intrinsic Disordered Region (IDR). A mutational screen reveals that mutations in critical residues in the MYC coiled-coil domain structurally adjacent to the IDR of MED30 strongly inhibit tumor growth, even in the presence of wild-type MED30, mimicking the effects of MED30 deletion. This study provides new insights into the principles governing the Mediator complex actions MYC-related biological processes.
2024-11-24 | GSE249335 | GEO
Project description:Despite extensive functional and structural investigation of the Mediator complex, the basis for selective functional requirements for specific Mediator subunits for the actions of specific DNA binding transcription factors remain incompletely understood. Here, we report the MED30 subunit of Mediator, one of the core subunits maintaining the complex, plays a critical role in regulating the MYC transcription program in cancer cells. This is consequent to MED30 being required for stabilizing Mediator complex and MYC binding on the genome, involving low-affinity hydrophobic interaction functions of the MYC N-terminal Intrinsic Disordered Region (IDR). A mutational screen reveals that mutations in critical residues in the MYC coiled-coil domain structurally adjacent to the IDR of MED30 strongly inhibit tumor growth, even in the presence of wild-type MED30, mimicking the effects of MED30 deletion. This study provides new insights into the principles governing the Mediator complex actions MYC-related biological processes.
2024-11-24 | GSE249178 | GEO
Project description:The Role of Mediator Subunit MED30 in Licensing the c-Myc Oncogenic Program [PRO-seq]
| PRJNA1047607 | ENA
Project description:The Role of Mediator Subunit MED30 in Licensing the c-Myc Oncogenic Program [RNA-seq]
| PRJNA1047610 | ENA
Project description:The Role of Mediator Subunit MED30 in Licensing the c-Myc Oncogenic Program [ChIP-seq]
| PRJNA1048545 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-11-24 | GSE249179 | GEO
Project description:Understanding the molecular mechanisms underlying tumorigenesis is crucial for developing effective cancer therapies. Here, we investigate the common co-amplification of MED30 and MYC across diverse cancer types and its impact on oncogenic transcriptional programs. Transcriptional profiling of MYC and MED30 single or both overexpression/amplification revealed the over amount of MED30 lead MYC to a new transcriptional program that associate with poor prognosis. Mechanistically, MED30 overexpression/amplification recruits other Mediator components and binding of MYC to a small subset of novel genomic regulatory sites, changing the epigenetic marks and inducing the formation of new enhancers, which drive the expression of target genes crucial for cancer progression. In vivo studies in pancreatic ductal adenocarcinoma (PDAC) further validate the oncogenic potential of MED30, as its overexpression promotes tumor growth and can be attenuated by knockdown of MYC. Using another cancer type, MED30 knockdown reduces tumor growth particularly in MYC high-expressed glioblastoma (GBM) cell lines. Overall, our study elucidates the critical role of MED30 overexprssion in orchestrating oncogenic transcriptional programs and highlights its potential as a therapeutic target for MYC-amplified cancer.
2024-05-30 | GSE264374 | GEO
Project description:Understanding the molecular mechanisms underlying tumorigenesis is crucial for developing effective cancer therapies. Here, we investigate the common co-amplification of MED30 and MYC across diverse cancer types and its impact on oncogenic transcriptional programs. Transcriptional profiling of MYC and MED30 single or both overexpression/amplification revealed the over amount of MED30 lead MYC to a new transcriptional program that associate with poor prognosis. Mechanistically, MED30 overexpression/amplification recruits other Mediator components and binding of MYC to a small subset of novel genomic regulatory sites, changing the epigenetic marks and inducing the formation of new enhancers, which drive the expression of target genes crucial for cancer progression. In vivo studies in pancreatic ductal adenocarcinoma (PDAC) further validate the oncogenic potential of MED30, as its overexpression promotes tumor growth and can be attenuated by knockdown of MYC. Using another cancer type, MED30 knockdown reduces tumor growth particularly in MYC high-expressed glioblastoma (GBM) cell lines. Overall, our study elucidates the critical role of MED30 overexprssion in orchestrating oncogenic transcriptional programs and highlights its potential as a therapeutic target for MYC-amplified cancer.
2024-05-30 | GSE264275 | GEO
Project description:Mediator Subunit 30 Directs Myc Oncogenesis
| PRJNA899516 | ENA