Brd4::Nutm1 fusion gene initiates NUT carcinoma in vivo [RNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1098066 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28601875_1.fastq.gz | Fastqsanger.gz | |||
| SRR28601875_2.fastq.gz | Fastqsanger.gz | |||
| SRR28601876_1.fastq.gz | Fastqsanger.gz | |||
| SRR28601876_2.fastq.gz | Fastqsanger.gz | |||
| SRR28601877_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 24 |
Similar Datasets
Project description:NUT carcinoma (NC) is an aggressive cancer with no effective treatment. About 70% of NUT carcinoma is associated with chromosome translocation events that lead to the formation of a BRD4::NUTM1 fusion gene. Because the BRD4::NUTM1 gene is unequivocally cytotoxic when ectopically expressed in cell lines, questions remain on whether the fusion gene can initiate NC. Here, we report the first genetically engineered mouse model (GEMM) for NUT carcinoma that recapitulates the t(15;19) chromosome translocation in mice. We demonstrated that the mouse t(2;17) syntenic chromosome translocation, forming the Brd4::Nutm1 fusion gene, could induce aggressive carcinomas in mice. The tumors present histopathological and molecular features similar to human NC, with an enrichment of undifferentiated cells. Similar to the reports of human NC incidence, Brd4::Nutm1 can induce NC from a broad range of tissues with a strong phenotypical variability. The consistent induction of poorly differentiated carcinoma demonstrated a strong reprogramming activity of BRD4::NUTM1. The new mouse model provided a critical preclinical model for NC that will lead to better understanding and therapy development for NC.
2024-05-07 | GSE263567 | GEO
Project description:NUT carcinoma (NC) is an aggressive cancer with no effective treatment. About 70% of NUT carcinoma is associated with chromosome translocation events that lead to the formation of a BRD4::NUTM1 fusion gene. Because the BRD4::NUTM1 gene is unequivocally cytotoxic when ectopically expressed in cell lines, questions remain on whether the fusion gene can initiate NC. Here, we report the first genetically engineered mouse model (GEMM) for NUT carcinoma that recapitulates the t(15;19) chromosome translocation in mice. We demonstrated that the mouse t(2;17) syntenic chromosome translocation, forming the Brd4::Nutm1 fusion gene, could induce aggressive carcinomas in mice. The tumors present histopathological and molecular features similar to human NC, with an enrichment of undifferentiated cells. Similar to the reports of human NC incidence, Brd4::Nutm1 can induce NC from a broad range of tissues with a strong phenotypical variability. The consistent induction of poorly differentiated carcinoma demonstrated a strong reprogramming activity of BRD4::NUTM1. The new mouse model provided a critical preclinical model for NC that will lead to better understanding and therapy development for NC.
2024-05-07 | GSE263558 | GEO
Project description:To investigate the mechanism that drives dramatic mistargeting of active chromatin in NUT midline carcinoma, we have identified protein interactions unique to the BRD4-NUT fusion oncoprotein compared to wild type BRD4. Using crosslinking, affinity purification, and mass spectrometry, we identified the EP300 acetyltransferase as uniquely associated with BRD4 through the NUT fusion in both NMC and non-NMC cell types. We also discovered ZNF532 among a small number of candidates associated with BRD4-NUT in NMC patient cells but not present in 293T cells.
2017-04-05 | PXD005786 | Pride
Project description:Aberrant formation of biomolecular condensates has been proposed to play a role in several cancers. The oncogenic fusion protein BRD4-NUT forms condensates and drives changes in gene expression in Nut Carcinoma (NC). Here we sought to understand the molecular elements of BRD4-NUT and its associated histone acetyltransferase (HAT), p300, that promote these activities. We determined that a minimal fragment of NUT (MIN) in fusion with BRD4 is necessary and sufficient to bind p300 and form condensates. Furthermore, a BRD4-p300 fusion protein also forms condensates and drives gene expression similarly to BRD4-NUT(MIN), suggesting the p300 fusion may mimic certain features of BRD4-NUT. The intrinsically disordered regions, transcription factor-binding domains, and HAT activity of p300 all collectively contribute to condensate formation by BRD4-p300, suggesting that these elements might contribute to condensate formation by BRD4-NUT. Conversely, only the HAT activity of BRD4-p300 appears necessary to mimic the transcriptional profile of cells expressing BRD4-NUT. Our results suggest a model for condensate formation by the BRD4-NUT:p300 complex involving a combination of positive feedback and phase separation, and show that multiple overlapping, yet distinct, regions of p300 contribute to condensate formation and transcriptional regulation.
2023-05-24 | GSE233301 | GEO
Project description:Aberrant formation of biomolecular condensates has been proposed to play a role in several cancers. The oncogenic fusion protein BRD4-NUT forms condensates and drives changes in gene expression in Nut Carcinoma (NC). Here we sought to understand the molecular elements of BRD4-NUT and its associated histone acetyltransferase (HAT), p300, that promote these activities. We determined that a minimal fragment of NUT (MIN) in fusion with BRD4 is necessary and sufficient to bind p300 and form condensates. Furthermore, a BRD4-p300 fusion protein also forms condensates and drives gene expression similarly to BRD4-NUT(MIN), suggesting the p300 fusion may mimic certain features of BRD4-NUT. The intrinsically disordered regions, transcription factor-binding domains, and HAT activity of p300 all collectively contribute to condensate formation by BRD4-p300, suggesting that these elements might contribute to condensate formation by BRD4-NUT. Conversely, only the HAT activity of BRD4-p300 appears necessary to mimic the transcriptional profile of cells expressing BRD4-NUT. Our results suggest a model for condensate formation by the BRD4-NUT:p300 complex involving a combination of positive feedback and phase separation, and show that multiple overlapping, yet distinct, regions of p300 contribute to condensate formation and transcriptional regulation.
2023-05-24 | GSE233302 | GEO
Project description:Discarded live tumor tissue from a metastatic focus in the patientM-bM-^@M-^Ys lung was collected under institutional review board approval through the NUT midline carcinoma registry (www.NMCRegistry.org). From this tissue the first known NUT-variant cell line, 1221, was established. To determine the putative partner gene to NUT, we performed comprehensive RNA-sequencing on RNA purified from 1221. We identified an in-frame transcript fusing the 5M-bM-^@M-^Y coding sequence of NSD3 (exons 1-7) to exons 2-7 of NUT. Expression of the NSD3-NUT fusion oncoprotein was verified by immunobloting with an antibody to NUT, revealing an approximately 200kDa band that is similar in size to BRD3-NUT, but smaller than BRD4-NUT Identification of a NUT fusion partner using RNA extracted from live cultured 1221 cell line derived from a lung metastasis from the index case of a 13 year old female with NUT-positive NMC.
2014-08-01 | E-GEOD-57222 | biostudies-arrayexpress
Project description:Discarded live tumor tissue from a metastatic focus in the patient’s lung was collected under institutional review board approval through the NUT midline carcinoma registry (www.NMCRegistry.org). From this tissue the first known NUT-variant cell line, 1221, was established. To determine the putative partner gene to NUT, we performed comprehensive RNA-sequencing on RNA purified from 1221. We identified an in-frame transcript fusing the 5’ coding sequence of NSD3 (exons 1-7) to exons 2-7 of NUT. Expression of the NSD3-NUT fusion oncoprotein was verified by immunobloting with an antibody to NUT, revealing an approximately 200kDa band that is similar in size to BRD3-NUT, but smaller than BRD4-NUT
2014-08-01 | GSE57222 | GEO
Project description:BRD4-NUT megadomains is an order of magnitude larger than super-enhancer regions and displays a more continuously enriched profile rather than appearing as a cluster of individual peaks. Chip-seq mapping of active chromatin marks in BRD4-NUT and different NMC cells
2015-07-14 | E-GEOD-70870 | biostudies-arrayexpress
Project description:To investigate the mechanism that drives dramatic mistargeting of active chromatin in NUT-midline carcinoma, we have identified protein interactions unique to the BRD4-NUT fusion oncoprotein compared to wild type BRD4. Using crosslinking, affinity purification, and mass spectrometry, we identify the p300 acetyltransferase as ectopically associated with BRD4 through the NUT fusion in both NMC and non-NMC cell types. We also identify ZNF532 among a number of candidates uniquely associated with BRD4-NUT in NMC patient cells but not present in 293T cells. p300 and ZNF532 are both implicated in feed-forward regulatory loops leading to propagation of the oncogenic regulatory complex in BRD4-NUT patient cells. Extending our biochemical findings, we independently identified a novel ZNF532-NUT translocation fusion in a newly diagnosed NMC patient. ChIP-seq of key players: NUT, ZNF532, BRD4, p300, and anti-H3K27ac, reveals the formation of ZNF532-NUT-associated hyperacetylated megadomains, distinctly localized, but otherwise analogous to those found in BRD4-NUT patient cells. Our results support a model in which NMC is caused by a cascade of misregulation that is initiated by ectopic protein-protein interactions on chromatin between NUT and several distinct, but interacting, components of BRD4 regulatory complexes.
2017-08-22 | GSE96775 | GEO