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A genetically engineered mouse model of NUT carcinoma (CUT&RUN)

ABSTRACT: We created a genetically engineered mouse model (GEMM) of NC that forms a Brd4-NUTM1 fusion gene upon tamoxifen-induction of Sox2-driven Cre. Two GEMM-derived cell lines were developed whose transcriptomic and epigenetic landscapes, characterized by RNAseq and CUT&RUN, show striking overlap with those of primary GEMM tumors. GEMM primary tumor and cell lines form very large H3K27ac-enriched super-enhancers that are unique to hNC, termed megadomains, that are invariably associated with key hNC-defining transcriptional oncogenic targets, Myc and Trp63.

ORGANISM(S): Mus musculus

PROVIDER: GSE241476 | GEO | 2023/10/04

REPOSITORIES: GEO

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A genetically engineered mouse model (GEMM) of NUT carcinoma (RNA-Seq)

Project description:NUT carcinoma (NC) is a highly aggressive subtype of squamous carcinoma driven by the BRD4-NUT fusion oncoprotein. Closely resembling human NC (hNC), GEMM tumors (mNC) are poorly differentiated squamous carcinomas that express high levels of MYC and metastasize to organs (liver, lung) and regional lymph nodes. Two GEMM-derived cell lines were developed whose transcriptomic and epigenetic landscapes, characterized by RNAseq and CUT&RUN, show striking overlap with those of primary GEMM tumors. As in hNC, BRD4-NUT functions to block differentiation and maintain growth of mNC, as evidenced by BRD4-NUT knockdown and treatment of mNC cell lines with BET bromodomain inhibitors (BETi). Mechanistically, GEMM primary tumor and cell lines form very large H3K27ac-enriched super-enhancers that are unique to hNC, termed megadomains, that are invariably associated with key hNC-defining transcriptional oncogenic targets, Myc and Trp63.

2023-10-04 | GSE241474 | GEO

Brd4::Nutm1 fusion gene initiates NUT carcinoma in vivo [WGS]

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

Brd4::Nutm1 fusion gene initiates NUT carcinoma in vivo [RNA-seq]

2024-05-07 | GSE263558 | GEO

ChIP-seq analysis of BRD4-NUT and H3K27ac distribution in NUT Carcinoma cell line TC-797 treated with DMSO or Panobinostat

Project description:BRD4-NUT and H3K27ac are depleted from megadomains in NUT Carcinoma (NC) cell line TC-797 after treatment with Panobinostat.

2021-07-14 | GSE179692 | GEO

Chip-seq mapping of active chromatin marks in BRD4-NUT and different NMC cells

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

Genomic Profiling of MYC in 797 cells containing BRD4-NUT with JQ1 treatment

Project description:The oncogene cMYC (HGNC ID: HGNC:7553) is a critical genomic target of the BRD4-NUT (B4N) protein that defines many of the NUTM1-rearrangement cancer subtypes. B4N interacts with the EP300 lysine acetyltransferase (KAT) to create hyperacetylated “megadomains” that activate downstream genes such as MYC. However, it is less well understood how mis-regulation of MYC in turn affects its protein interactions and target genes. The goals of this study are to define the protein and genomic interactions of MYC in NUT carcinoma, and to test whether those change in response to B4N inactivation. We used CRISPR-Cas9 mediated knock-in of a BioTAP affinity tag to analyze MYC protein expressed from its normal chromosomal context. This allowed us to adapt a crosslinking purification method termed BioTAP-XL to preserve MYC integrity and chromatin association for genomic and mass spectrometry-based proteomic analyses. We found that MYC interacts primarily with NuA4 KAT subunits and that the interactions were maintained despite a decrease in MYC levels after JQ1 treatment. We propose that future analysis of MYC transcriptional regulation in NUT carcinoma, and likely other cancers, should prioritize how MYC recruits KAT complexes to modify the chromatin of its many gene targets.

2022-04-27 | GSE201033 | GEO

Chip-seq mapping of active chromatin marks in BRD4-NUT and different NMC cells

2015-07-14 | GSE70870 | GEO

Homo sapiens

Project description:Genetic profiling of HNC cell lines

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Single cell RNA sequencing profiles on whole tumors from a Kras/Rnf43 genetically engineered mouse model of pancreatic adenocarcinoma

Project description:We report single cell RNA sequencing of pancreatic enzymatically digested whole, fresh tumors from a genetically engineered mouse model (GEMM) of pancreatic adenocarcinoma. This GEMM consists of pancreas specific expression of oncogenic Kras (Kras-G12D) in addition of homozygous deletion of the ring finger domain (catalytic domain) of Rnf43. This GEMM is termed 'KRC'.

2022-03-23 | GSE188946 | GEO

siRNA silencing of p63 (trp63) in human primary keratinocytes via siRNA oligo transfection.

Project description:Genome-wide identification of bona fide targets of transcription factors in mammalian cells is still a challenge. We present a novel integrated computational and experimental approach to identify direct targets of a transcription factor. This consists in measuring time-course (dynamic) gene expression profiles upon perturbation of the transcription factor under study, and in applying a novel reverse-engineeringâ algorithm (TSNI) to rank genes according to their probability of being direct targets. Using primary keratinocytes as a model system, we identified novel transcriptional target genes of Trp63, a crucial regulator of skin development. TSNI-predicted Trp63 target genes were validated by Trp63 knockdown and by ChIP-chip to identify Trp63-bound regions in vivo. Our study revealed that short sampling times, in the order of minutes, are needed to capture the dynamics of gene expression in mammalian cells. We show that Trp63 transiently regulates a subset of its direct targets, thus highlighting the importance of considering temporal dynamics when identifying transcriptional targets. Using this approach, we uncovered a previously unsuspected transient regulation of the AP-1 complex by Trp63, through direct regulation of a subset of AP-1 components. The integrated experimental and computational approach described here is readily applicable to other transcription factors in mammalian systems and is complementary to genome-wide identification of transcription factor binding sites. Experiment Overall Design: Transient transfection of primary keratinocytes with Trp63-specific small interfering RNA oligonucleotides. Cell were collected 48h after transfection.

2008-04-06 | E-GEOD-10564 | biostudies-arrayexpress

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