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The USP11/TCEAL1 complex promotes transcription elongation to sustain oncogenic gene expression in neuroblastoma [RNA-seq II]

ABSTRACT: The USP11/TCEAL1 complex promotes transcription elongation to sustain oncogenic gene expression in neuroblastoma [RNA-seq II]

PROVIDER: PRJNA1250445 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR33121826_1.fastq.gz	Fastqsanger.gz
	SRR33121826_2.fastq.gz	Fastqsanger.gz
	SRR33121827_1.fastq.gz	Fastqsanger.gz
	SRR33121827_2.fastq.gz	Fastqsanger.gz
	SRR33121828_1.fastq.gz	Fastqsanger.gz

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The USP11/TCEAL1 complex promotes transcription elongation to sustain oncogenic gene expression in neuroblastoma [ChIP-seq II]

Project description:During early transcription, RNA polymerase II (RNAPII) undergoes a series of structural transitions controlled by cyclin-dependent kinases. How protein ubiquitylation and proteasomal degradation control the function of RNAPII is less well understood. Here we show that the deubiquitinating enzyme USP11 forms a complex with TCEAL1, a member of the TFIIS (TCEA)-like protein family. TCEAL1 shares sequence homology with the RNAPII interaction domain of the elongation factor TFIIS, which controls the fate of backtracked RNAPII, and competes with TFIIS for binding to core promoters, potentially preventing excessive backtracking. USP11 protects TCEAL1 from proteasomal degradation and TCEAL1 recruits USP11 to RNAPII. Both USP11 and TCEAL1 promote transcription elongation and maintain expression of RPB8, an essential subunit of all three nuclear RNA polymerases. In neuroblastoma USP11- and TCEAL1-dependent genes define a gene expression program that is characteristic for mesenchymal tumors, which are described to escape from many treatments, suggesting that the USP11/TCEAL1 complex promotes transcription elongation to support a critical oncogenic gene expression program

2025-04-25 | GSE294527 | GEO

The USP11/TCEAL1 complex promotes transcription elongation to sustain oncogenic gene expression in neuroblastoma [RNA-seq II]

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A trimeric USP11-USP7-TCEAL1 complex stabilizes paused RNAPII to sustain oncogenic transcription [ChIP-seq]

Project description:During early transcription, RNA polymerase II (RNAPII) undergoes a series of structural transitions controlled by cyclin-dependent kinases. Whether protein ubiquitylation and proteasomal degradation affect the fate of RNAPII at core promoters is less well understood. Here we show that the deubiquitinating enzyme USP11 and its heterodimeric partner USP7 form a trimeric complex with TCEAL1, a member of the poorly understood TCEAL (TCEA/TFIIS-like) protein family. TCEAL1 shares sequence homology with the RNAPII interaction domain of the TCEA/TFIIS elongation factor, which controls the fate of backtracked RNAPII. TCEAL1 stabilizes complexes of USP11 with USP7 and with RNAPII. TCEAL1 is recruited to core promoters upon RNAPII pausing and globally enhances the chromatin association of paused RNAPII. Mechanistically, the USP11/USP7/TCEAL1 complex competes with TFIIS for binding to core promoters and protects RPB8, an essential subunit of RNAPII, from degradation, likely preventing TFIIS-mediated transcript cleavage and RNAPII disassembly. In neuroblastoma and other tumors, TCEAL1-dependent genes define a TGF-beta-dependent gene expression program that is characteristic of mesenchymal and invasive tumor cell types, suggesting that the USP11/USP7/TCEAL1 trimer stabilizes paused RNAPII to support a critical oncogenic gene expression program.

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A trimeric USP11-USP7-TCEAL1 complex stabilizes paused RNAPII to sustain oncogenic transcription [RNA-seq]

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The USP11/TCEAL1 complex promotes transcription elongation to sustain oncogenic gene expression in neuroblastoma [ChIP-seq II]

Project description:The USP11/TCEAL1 complex promotes transcription elongation to sustain oncogenic gene expression in neuroblastoma [ChIP-seq II]

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A trimeric USP11-USP7-TCEAL1 complex stabilizes paused RNAPII to sustain oncogenic transcription

Project description:A trimeric USP11-USP7-TCEAL1 complex stabilizes paused RNAPII to sustain oncogenic transcription

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A trimeric USP11-USP7-TCEAL1 complex stabilizes paused RNAPII to sustain oncogenic transcription [RNA-seq]

Project description:A trimeric USP11-USP7-TCEAL1 complex stabilizes paused RNAPII to sustain oncogenic transcription [RNA-seq]

| PRJNA1141427 | ENA

A trimeric USP11-USP7-TCEAL1 complex stabilizes paused RNAPII to sustain oncogenic transcription [ChIP-seq]

Project description:A trimeric USP11-USP7-TCEAL1 complex stabilizes paused RNAPII to sustain oncogenic transcription [ChIP-seq]

| PRJNA1141429 | ENA

The Super Elongation Complex Drives Transcriptional Addiction in MYCN-amplified Neuroblastoma

Project description:MYCN amplification in neuroblastoma leads to aberrant expression of MYCN oncoprotein, which binds active genes promoting transcriptional amplification. Yet how MYCN coordinates transcription elongation to meet productive transcriptional amplification and which elongation machinery represents MYCN-driven vulnerability remain to be identified. We conducted a targeted screen of transcription elongation factors and identified the super elongation complex (SEC) as a unique vulnerability in MYCN-amplified neuroblastomas. MYCN directly binds EAF1 and recruits SEC to enhance processive transcription elongation. Depletion of EAF1 or AFF1/AFF4, another core subunit of SEC, leads to a global reduction in transcription elongation and elicits selective apoptosis of MYCN-amplified neuroblastoma cells. A combination screen reveals SEC inhibition synergistically potentiates the therapeutic efficacies of FDA-approved BCL2 antagonist ABT-199, in part due to suppression of MCL1 expression, both in MYCN-amplified neuroblastoma cells and in patient-derived xenografts. These findings identify disruption of the MYCN-SEC regulatory axis as a promising therapeutic strategy in neuroblastoma.

2023-05-10 | PXD039332 | Pride

Targeting Transcriptional Addiction in MYCN-amplified Neuroblastoma via Super Elongation Complex Disruption

Project description:MYCN amplification in neuroblastoma predicts particular poor prognosis and directly targeting of MYCN remains a major challenge. We conducted a targeted screen of transcription elongation factors and identified the super elongation complex (SEC) as a unique vulnerability in MYCN-amplified neuroblastoma. Mechanistically, MYCN directly interacts with the SEC subunit EAF1 and recruits the complex to the target gene loci for ensuing processive transcription elongation, rendering MYCN-mediated transcriptional activation highly dependent on SEC. Pharmacological inhibition of SEC by KL-1 or KL-2 elicits selective cell death in MYCN-overexpressing neuroblastoma cells. Furthermore, drug combination screening identifies the BCL-2 inhibitor ABT-199 synergistic with KL-2. Pre-clinical studies manifest that KL-2 and ABT-199 co-treatment significantly suppresses tumorigenesis and shows therapeutic value in multiple neuroblastoma allograft and xenograft models. These findings highlight SEC as a targetable vulnerability, and simultaneous inhibition of SEC and BCL-2 holds great promise for the treatment of MYCN-driven neuroblastoma.

2023-02-27 | GSE199086 | GEO

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