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Targeted brachyury degradation disrupts a highly specific autoregulatory program controlling chordoma cell identity

ABSTRACT: Targeted brachyury degradation disrupts a highly specific autoregulatory program controlling chordoma cell identity

PROVIDER: PRJNA644626 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12168600.fastq.gz	Fastqsanger.gz
	SRR12168601.fastq.gz	Fastqsanger.gz
	SRR12168602.fastq.gz	Fastqsanger.gz
	SRR12168603.fastq.gz	Fastqsanger.gz
	SRR12168604.fastq.gz	Fastqsanger.gz

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Targeted brachyury degradation disrupts a highly specific autoregulatory program controlling chordoma cell identity [ChIPmentation]

Project description:Chordomas are rare spinal tumors addicted to expression of the developmental transcription factor brachyury. In chordomas, brachyury is super-enhancer associated and preferentially downregulated by pharmacologic transcriptional CDK inhibition, leading to cell death. To understand the underlying basis of this sensitivity, we dissect the brachyury transcription regulatory network and compare the consequences of brachyury degradation with transcriptional CDK inhibition. Brachyury defines the chordoma super-enhancer landscape and autoregulates through binding its super-enhancer, and its locus forms a transcriptional condensate. Transcriptional CDK inhibition and brachyury degradation disrupt brachyury autoregulation, leading to loss of its transcriptional condensate and transcriptional program. Compared with transcriptional CDK inhibition, which globally downregulates transcription, leading to cell death, brachyury degradation is much more selective, inducing senescence and sensitizing cells to anti-apoptotic inhibition. These data suggest that brachyury downregulation is a core tenet of transcriptional CDK inhibition and motivates developing strategies to target brachyury and its autoregulatory feedback loop.

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Targeted brachyury degradation disrupts a highly specific autoregulatory program controlling chordoma cell identity [Total RNA-seq, SLAM-seq]

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Targeted brachyury degradation disrupts a highly specific autoregulatory program controlling chordoma cell identity [ChIPmentation]

Project description:Targeted brachyury degradation disrupts a highly specific autoregulatory program controlling chordoma cell identity [ChIPmentation]

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Targeted brachyury degradation disrupts a highly specific autoregulatory program controlling chordoma cell identity [Total RNA-seq, SLAM-seq]

Project description:Targeted brachyury degradation disrupts a highly specific autoregulatory program controlling chordoma cell identity [Total RNA-seq, SLAM-seq]

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Targeted brachyury degradation disrupts a highly specific autoregulatory program controlling chordoma cell identity.

| S-EPMC7817874 | biostudies-literature

Brachyury ChIP sequencing of human chordoma UCH-1 cell line

Project description:ChIP sequencing of chordoma UCH-1 cell line. A well characterised chordoma cell line which bears all the morphological and immunohistochemical features of a chordoma (large vacuolated slow-growing cells, brachyury and cytokeratin-positive) have been used in this study. Chromatin immunoprecipitation using a well characterised anti-Brachyury antibody which has been used in immunohistochemistry of chordoma samples and previous ChIP studies in other systems. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

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Targeted brachyury degradation disrupts a highly specific autoregulatory program controlling chordoma cell identity

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

2021-02-08 | GSE153973 | GEO

Small-molecule targeting of brachyury transcription factor addiction in chordoma [rnaseq_compound]

Project description:Chordoma is a primary bone cancer with no approved therapy. The identification of therapeutic targets in this disease has been challenging due to the infrequent occurrence of clinically actionable somatic mutations in chordoma tumors. Here we describe the discovery of therapeutically targetable chordoma dependencies via genome-scale CRISPR-Cas9 screening and focused small-molecule sensitivity profiling. These systematic approaches reveal that the developmental transcription factor T (brachyury; TBXT) is the top selectively essential gene in chordoma, and that transcriptional cyclin-dependent kinase (CDK) inhibitors targeting CDK7/12/13 and CDK9 potently suppress chordoma cell proliferation. In other cancer types, transcriptional CDK inhibitors have been observed to downregulate highly expressed, enhancer-associated oncogenic transcription factors (TFs). In chordoma, we find that T is associated with a 1.5-Mb region containing “super-enhancers” and is the most highly expressed super-enhancer-associated TF. Strikingly, transcriptional CDK inhibition leads to preferential and concentration-dependent downregulation of cellular brachyury protein levels in all models tested. Together, these data demonstrate small-molecule targeting of brachyury TF addiction in chordoma, identify a mechanism of T gene regulation that underlies this therapeutic strategy and provide a blueprint for applying systematic genetic and chemical screening approaches to discover vulnerabilities in genomically quiet cancers.

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