Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Regulation of melanoma cellular plasticity by the Mediator complex drives therapeutic resistance [ChIP-Seq]

ABSTRACT: Melanoma exhibits profound cellular plasticity that enables adaptive responses to therapeutic pressure and ultimately drives treatment resistance. However, the transcriptional mechanisms governing melanoma cell-state transitions remain incompletely understood. Here, we identify the Mediator complex as a central regulator of melanoma cellular plasticity that promotes resistance to targeted therapy. Using genetic and pharmacological perturbations, we show that disruption of Mediator function induces melanoma cell-state switching, promotes dedifferentiation programs, characterized by loss of lineage-specific transcriptional programs and activation of survival-associated gene expression, and enhances resistance to MAPK pathway inhibition. Mechanistically, Mediator tail depletion rewires transcriptional networks governing cell identity and adaptive signaling, enabling melanoma cells to bypass MAPK pathway blockade. Collectively, our findings identify the Mediator tail module as a key transcriptional safeguard against melanoma dedifferentiation and reveal its unexpected role in suppressing cellular plasticity–driven resistance to targeted therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE316620 | GEO | 2026/04/29

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Regulation of melanoma cellular plasticity by the Mediator complex drives therapeutic resistance [persister]

Project description:Melanoma exhibits profound cellular plasticity that enables adaptive responses to therapeutic pressure and ultimately drives treatment resistance. However, the transcriptional mechanisms governing melanoma cell-state transitions remain incompletely understood. Here, we identify the Mediator complex as a central regulator of melanoma cellular plasticity that promotes resistance to targeted therapy. Using genetic and pharmacological perturbations, we show that disruption of Mediator function induces melanoma cell-state switching, promotes dedifferentiation programs, characterized by loss of lineage-specific transcriptional programs and activation of survival-associated gene expression, and enhances resistance to MAPK pathway inhibition. Mechanistically, Mediator tail depletion rewires transcriptional networks governing cell identity and adaptive signaling, enabling melanoma cells to bypass MAPK pathway blockade. Collectively, our findings identify the Mediator tail module as a key transcriptional safeguard against melanoma dedifferentiation and reveal its unexpected role in suppressing cellular plasticity–driven resistance to targeted therapy.

2026-04-29 | GSE316898 | GEO

Regulation of melanoma cellular plasticity by the Mediator complex drives therapeutic resistance [crispr]

2026-04-29 | GSE316897 | GEO

Regulation of melanoma cellular plasticity by the Mediator complex drives therapeutic resistance [ATAC-Seq]

2026-04-29 | GSE316797 | GEO

Regulation of melanoma cellular plasticity by the Mediator complex drives therapeutic resistance

2026-04-29 | GSE316474 | GEO

The CoREST Repressor Complex Mediates Phenotype Switching and Therapy Resistance in Melanoma [ChIP-seq]

Project description:Virtually all patients with BRAF-mutant melanoma develop resistance to MAPK inhibitors largely through non-mutational events. Although the epigenetic landscape is shown to be altered in therapy-resistant melanomas and other cancers, a specific targetable epigenetic mechanism has not been validated to date. Here, we evaluate the CoREST repressor complex and the recently developed bivalent inhibitor, corin, within the context of melanoma phenotype plasticity and therapeutic resistance. We find that CoREST is a critical mediator of the major distinct melanoma phenotypes and that corin treatment of melanoma cells leads to phenotype reprogramming. Global assessment of transcript and chromatin changes conferred by corin reveals specific effects on histone marks connected to EMT-associated transcription factors and the dual-specificity phosphatases (DUSPs). Remarkably, treatment of BRAF inhibitor (BRAFi)-resistant melanomas with corin promotes resensitization to BRAFi therapy. DUSP1 is consistently downregulated in BRAFi-resistant melanomas which is reversed by corin treatment and associated with inhibition of p38 MAPK activity and resensitization to BRAFi therapies. Moreover, this activity can be recapitulated by the p38 MAPK inhibitor, BIRB 796. These findings identify the CoREST repressor complex as a central mediator of melanoma phenotype plasticity and resistance to targeted therapy and suggest that CoREST inhibitors may prove beneficial to patients with BRAFi- resistant melanoma.

2024-02-22 | GSE254701 | GEO

The CoREST Repressor Complex Mediates Phenotype Switching and Therapy Resistance in Melanoma

2024-02-01 | GSE156250 | GEO

Genome-wide maps of transcriptomic and epigenomic state in melanoma cell lines

Project description:A mechanistic relationship between tumor epigenetic plasticity and nongenetic adaptive resistance to therapy is described, with MAPK inhibition of BRAF-mutant melanoma cells providing the model system. Upon inhibition, these largely melanocytic cells undergo reversible cell-state changes, ultimately yielding a drug-resistant mesenchymal-like phenotype. Epigenomic and transcriptomic kinetic studies, coupled with information theory and dynamic system modeling, revealed that, after just 3-days of treatment, RelA drives chromatin remodeling to establish an epigenetic program encoding long-term phenotype changes. Specifically, RelA transcriptionally inhibits SOX10 and NFKBIE through recruiting KDM5B and HDAC1 to down-regulate histone marks H3K4me3 and H3K27ac at their promoter regions. Suppression of SOX10 mediates melanoma regression towards drug-refractory phenotypes. These findings were confirmed in melanoma patients under MAPK inhibitor treatment, providing mechanistic insights into resistance-leading epigenetic reprogramming triggered following drug exposure.

2026-03-31 | GSE255263 | GEO

Genome-wide maps of transcriptomic and epigenomic state in melanoma cell lines

2019-09-23 | GSE134459 | GEO

ZEB1 controls a lineage-specific transcriptional program essential for melanoma cell state transitions [ChIP-seq]

Project description:Cell plasticity sustains intra-tumor heterogeneity and treatment resistance in melanoma. Deciphering the transcriptional mechanisms governing reversible phenotypic transitions between proliferative/differentiated and invasive/stem-like states is required. Expression of the ZEB1 transcription factor is frequently activated in melanoma, where it fosters adaptive resistance to targeted therapies. Here, we performed a genome-wide characterization of ZEB1 transcriptional targets, by combining ChIP-sequencing and RNA-sequencing, upon phenotype switching in melanoma models. We identified and validated ZEB1 binding peaks in the promoter of key lineage-specific genes crucial for melanoma cell identity. Mechanistically, ZEB1 negatively regulates SOX10-MITF dependent proliferative/melanocytic programs and positively regulates AP-1 driven invasive and stem-like programs. Comparative analyses with breast carcinoma cells revealed lineage-specific ZEB1 binding, leading to the design of a more reliable melanoma-specific ZEB1 regulon. We then developed single-cell spatial multiplexed analyses to characterize melanoma cell states intra-tumoral heterogeneity in human melanoma samples. Combined with scRNA-Seq analyses, our findings confirmed increased ZEB1 expression in Neural-Crest-like cells and mesenchymal cells, underscoring its significance in vivo in both populations. Overall, our results define ZEB1 as a major transcriptional regulator of cell states transitions and provide a better understanding of lineage-specific transcriptional programs sustaining intra-tumor heterogeneity in melanoma.

2024-03-26 | GSE246672 | GEO

ZEB1 controls a lineage-specific transcriptional program essential for melanoma cell state transitions [RNA-seq]

2024-03-26 | GSE246603 | GEO