Targeted brachyury degradation disrupts a highly specific autoregulatory program controlling chordoma cell identity
Hadley E Sheppard1, Alessandra Dall'Agnese2, Woojun D Park1
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Abstract:
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.
Insights
Chordomas rely on the brachyury transcription factor. Inhibiting CDK in chordoma cells downregulates brachyury, causing cell death, but targeting brachyury directly is more selective.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Chordomas are rare spinal tumors driven by the transcription factor brachyury.
- Brachyury expression is essential for chordoma cell survival and is associated with super-enhancers.
- Pharmacologic inhibition of Cyclin-Dependent Kinases (CDKs) downregulates brachyury, leading to cell death.
Purpose of the Study:
- To investigate the brachyury transcription regulatory network in chordomas.
- To compare the effects of brachyury degradation with global transcriptional CDK inhibition.
- To understand the molecular basis of chordoma sensitivity to CDK inhibition.
Main Methods:
- Dissection of the brachyury transcription regulatory network.
- Comparison of brachyury degradation versus transcriptional CDK inhibition.
- Analysis of transcriptional condensates and autoregulation.
Main Results:
- Brachyury controls the chordoma super-enhancer landscape and autoregulates its own expression.
- Both CDK inhibition and brachyury degradation disrupt brachyury autoregulation and its transcriptional condensate.
- Brachyury degradation selectively induces senescence and sensitizes cells to anti-apoptotic drugs, unlike global CDK inhibition.
Conclusions:
- Brachyury downregulation is a key mechanism of transcriptional CDK inhibition in chordomas.
- Targeting brachyury and its autoregulatory feedback loop offers a more selective therapeutic strategy.
- Selective targeting of brachyury may overcome limitations of global transcriptional inhibition.
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