Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE201033 | GEO | 2022/04/27

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Chromatin-associated protein interactions drive megadomain formation in NUT midline carcinoma

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

Transient Transcriptome Sequencing (TT-seq) of Nascent Gene Expression upon BRD4-NUT Protein Degradation/Recovery and RNA Polymerase II Inhibition

Project description:Delineating how chromosomes fold at length scales beyond one megabase remains obscure relative to smaller-scale folding into TADs, loops, and nucleosomes. We find that rather than simply unfolding chromatin, histone hyperacetylation results in interactions between distant genomic loci separated by tens to hundreds of megabases, even in the absence of transcription. These hyperacetylated “megadomains” are formed by the BRD4-NUT fusion oncoprotein, interact both within and between chromosomes, and form a specific nuclear subcompartment that has elevated gene activity with respect to other subcompartments. Pharmacological degradation of BRD4-NUT results in collapse of megadomains and attenuation of the interactions between them. In contrast, these interactions persist and contacts between newly acetylated regions are formed after inhibiting RNA polymerase II initiation. Our structure-function approach thus reveals that broad chromatin domains of identical biochemical composition, independent of transcription, form nuclear subcompartments, and also indicates the potential of altering chromosome structure for treating human disease.

2020-04-01 | GSE133164 | GEO

Hi-C to Identify Interactions between Distant Genomic Loci due to BRD4-NUT-mediated Megadomain Formation

2020-04-01 | GSE133163 | GEO

ChIP-seq Profiling of Histone H3K27ac, BRD4-NUT, and RNA Polymerase II Chromatin Localization During Megadomain Formation/Removal and RNA Polymerase II Inhibition

2020-04-01 | GSE133122 | 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

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

Chip-seq BRD4NUT-BioTAP mapping in 293Trex and 797 cells

2015-07-14 | E-GEOD-70869 | biostudies-arrayexpress