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

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

PROVIDER: PRJNA1071542 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27799117_1.fastq.gz	Fastqsanger.gz
	SRR27799117_2.fastq.gz	Fastqsanger.gz
	SRR27799118_1.fastq.gz	Fastqsanger.gz
	SRR27799118_2.fastq.gz	Fastqsanger.gz
	SRR27799119_1.fastq.gz	Fastqsanger.gz

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

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

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

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

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.

2024-02-01 | GSE156250 | GEO

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

2024-02-22 | GSE254701 | GEO

The CoREST repressor complex mediates phenotype switching and therapy resistance in melanoma.

Project description:Virtually all patients with BRAF-mutant melanoma develop resistance to MAPK inhibitors largely through nonmutational 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. Here, we evaluated the corepressor for element 1-silencing transcription factor (CoREST) epigenetic repressor complex and the recently developed bivalent inhibitor corin within the context of melanoma phenotype plasticity and therapeutic resistance. We found that CoREST was a critical mediator of the major distinct melanoma phenotypes and that corin treatment of melanoma cells led to phenotype reprogramming. Global assessment of transcript and chromatin changes conferred by corin revealed specific effects on histone marks connected to epithelial-mesenchymal transition-associated (EMT-associated) transcription factors and the dual-specificity phosphatases (DUSPs). Remarkably, treatment of BRAF inhibitor-resistant (BRAFi-R) melanomas with corin promoted resensitization to BRAFi therapy. DUSP1 was consistently downregulated in BRAFi-R melanomas, which was reversed by corin treatment and associated with inhibition of p38 MAPK activity and resensitization to BRAFi therapies. Moreover, this activity was 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 for patients with BRAFi-resistant melanoma.

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-02-05 | GSE254703 | GEO

Molecular switching of a DNA-sliding clamp to a repressor mediates long-range gene silencing

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ADAM19 Mediates Cellular Senescence and the Senescence-Associated Secretory Phenotype

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Proximity-dependent biotin identification (BioID) reveals a dynamic LSD1-CoREST interactome during embryonic stem cell differentiation

Project description:Lysine specific demethylase 1 (LSD1/KDM1A) regulates gene expression as part of the CoREST complex, along with co-repressor of REST (CoREST) and histone deacetylase 1 (HDAC1). CoREST is recruited to specific genomic loci by components of the core complex and numerous transient interactions with chromatin associated factors and transcription factors. To sample the chromatin environment in proximity to CoREST, we performed proximity-dependent biotin-identification (BioID) with four different members of the complex in 293T cells. Retaining only targets identified with 3 out of 4 baits, we identified 302 CoREST-associated proteins. Among this group were 16 of 18 known CoREST components and numerous novel associations, including readers (CHD3, 4, 6, 7 and 8), writers (KMT2B and KMT2D) and erasers (KDM2B) of histone methylation. However, components of other HDAC1 containing complexes (e.g. Sin3A, NuRD) were largely absent, suggesting that CoREST functions independently. As LSD1 plays an essential role in early embryonic development, we performed BioID using the endogeneously tagged protein in pluripotent, early- and late-differentiating embryonic stem cells. We identified 157 LSD1-associated proteins of which 66 were constitutively associated across all three time-points (44%), including novel interactions with the MMB and ChAHP complexes. These data imply that the majority of CoREST interactions are dynamic and highly cell type dependent.

2021-11-03 | PXD017344 | Pride

Molecular switching of a DNA-sliding clamp to a repressor mediates long-range gene silencing

Project description:Long-range gene regulation is rare in bacteria and is confined to the classical DNA looping model. Here, we use a combination of biophysical approaches, including X-ray crystallography and single-molecule analysis, to show that long-range gene silencing on the plasmid RK2, a source of multidrug resistance across diverse Gram-negative bacteria, is achieved cooperatively by a DNA-sliding clamp, KorB, and a clamp-locking protein, KorA. We find that KorB is a CTPase clamp that can entrap and slide along DNA to reach distal target promoters. We resolved the tripartite crystal structure of a KorB-KorA-DNA co-complex, revealing that KorA latches KorB into a closed-clamp state. KorA thus stimulates repression by stalling KorB sliding at target promoters to occlude RNA polymerase holoenzymes. Altogether, our findings explain the mechanistic basis for KorB role-switching from a DNA-sliding clamp to a co-repressor, and provide a new paradigm for the long-range regulation of gene expression.

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