The oncogenic BRD4-NUT chromatin regulator drives aberrant transcription within large topological domains
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Peter Kharchenko
PROVIDER: E-GEOD-70868 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
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: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 BRD4NUT-BioTAP mapping in 293Trex and 797 cells
2015-07-14 | E-GEOD-70869 | biostudies-arrayexpress
Project description:Nascent transcription profiles are shown for scaled megadomains and 100kb flanking regions before BRD4-NUT induction (0h) and at different time points (2h, 3h, 7h) following induction in 293T cells. Increase of the transcription from 0h to 7h after induction. Average level of transcriptional activity is reduced within the megadomains and their flanking regions following JQ1 treatment of TC-797 cells. Profile of nascent RNA-seq is shown for cells without JQ1 treatment, and for cells 1hr, 2.5hr and 4hr following JQ1 treatment. Recovery and analysis of nascent RNA
2015-07-14 | E-GEOD-70871 | biostudies-arrayexpress
Project description:Knockdown of the oncogene, BRD4-NUT, in a rare cancer, termed NUTmidline carcinoma (NMC), results in morphologic features consistent with squamous differentiation. Treatment with the HDAC-inhibitor, TSA, appears to cause the same phenotype. Here, we use gene expression profiling to compare the changes in gene expression following BRD4-NUT knockdown and TSA treatment. RNA was extracted from two BRD4-NUT-expressing NMC cell lines, PER-403 and TC-797, 24h following siRNA knockdown versus control in duplicate. RNA was extracted from two BRD4-NUT-expressing NMC cell lines, PER-403 and TC-797, 24h following treatment with TSA versus etoh control in triplicate
2011-07-01 | E-GEOD-18668 | biostudies-arrayexpress
Project description:Dosage compensation in D. melanogaster males is achieved via targeting of the MSL complex to X chromosomal genes. This is proposed to involve initial sequence-specific recognition of the X at ~150-300 chromatin entry sites, and subsequent spreading to nearby active genes. Here we test a model in which the spreading step requires transcription and is sequence-independent. We ask whether, in the native context of the X chromosome, MSL complex will target genes of autosomal origin. We find that MSL complex does bind such genes, but only if transcriptionally active. Targeting is accompanied by acetylation of the histone H4K16 residue and two-fold transcriptional up-regulation. We conclude that the presence of a long-sought specific DNA sequence within X-linked genes is not obligatory for MSL complex binding. Instead, physical linkage and transcription play the pivotal roles in the identification of MSL targets irrespective of their origin and DNA sequence. Keywords: Epigenetics ChIP-seq measurements of MSL complex binding and input control. Chromatin was prepared from third instar male larvae of a genotype y w TrojanElephant; MSL3-TAP; msl3. TrojanElephant is a mini-white- and yellow-marked transposition of genomic region spanning 65 kb from cg13773 to snRNP70K. MSL3-TAP is a mini-white-marked TAP-tagged genomic msl3 transgene. IgG beads were used for pull-down.
2009-08-20 | E-GEOD-17729 | biostudies-arrayexpress
Project description:The mitosporic fungus Trichoderma reesei is an industrial producer of enzymes for degradation of lignocellulosic polysaccharides to soluble monomers that can be fermented to biofuels. The genes encoding these enzymes in T. reesei have recently been shown to be clustered in the genome. Here we will show that the expression of these genes is epigenetically controlled at the heterochromatin level by the protein methyltransferase LAE1. Deletion of lae1 led to a loss of expression of the major cellulase and hemicellulase encoding genes, and resulted in an inability to grow on cellulose. The cellulase null phenotype was also seen with known soluble inducers of enzymes active on cellulose. In contrast, introduction of a second copy of lae1 or its enhanced expression under a strong constitutive promoter resulted in increased levels of cellulases. Thus, our data provides an experiment-based explanation for the advantage for clustering of cellulases in the genome of T. reesei, and imply that the heterochromatin structure is a major determinant of cellulase gene expression and hence an attractive target for strain improvement. We used two biological replicas of four T. reesei strains growing on lactose, the parent strain (QM9414), a delta-lae1, and two overexpressing strains (tef1:lae1 mutant 1 and mutant 2).
2011-01-01 | E-GEOD-22687 | biostudies-arrayexpress
Project description:Genomic analysis of control and collateral arteries was used to investigate mechanisms responsible for impaired collateral growth in the Spontaneously Hypertensive rat, an animal model of essential hypertension with increased oxidative and nitrosative stress and metabolic abnormalities. A fundamental difference was observed in the overall expression pattern in SHR vs WKY collaterals. Redox related genes with altered expression included cyba (the gene encoding p22phox), superoxide dismutase 3, and thioredoxin reductases 1 and 2. Cystatin C, hevin, angiotensinogen, and the angiotensin type 1b receptor (AT1bR) had altered collateral expression that was confirmed by RT-PCR. These molecules are known to have significant roles in other types of arterial remodeling. Of specific interest was the AT1bR which exhibited up-regulation in WKY collaterals, but down-regulation in SHR. A remarkable increase in AT1R protein was observed in WKY but not SHR collaterals. Pharmacological blockade of the AT1R with losartan prevented collateral luminal expansion in WKY. In SHR, captopril restored redox status assessed by cyba expression and nitric oxide concentration, prevented collateral AT1bR down-regulation and re-established the capacity for collateral growth. These results indicate that redox-status significantly alters flow-mediated transcriptional regulation and demonstrate that increased flow-related expression/activation of the AT1R is required for normal collateral luminal expansion but is altered by chronic oxidative and/or nitrosative stress in hypertensive rats. Keywords: gene expression two strains: two vessel types
2010-12-15 | E-GEOD-19524 | biostudies-arrayexpress
Project description:Novel genetic pathways associated with successful and/or unsuccessful vascular aging Customized therapies for vascular disease will require matching the vessel type and genetic background of the patient. Our previous studies showed that progressive age-related vascular pathology is strain specific in the thoracic aorta (TA) and mesenteric arteries (MA) of the Brown Norway (BN) and the Fisher344/Brown Norway F1 hybrid (F1) rats. The purpose of this study was to identify novel genetic pathways associated with successful and/or unsuccessful vascular aging. TA and MA were collected from anesthetized 6, 15 and 24 month old age-matched F1 and BN rats for total RNA isolation. The gene microarrays were generated using the Affimetrix GeneChip Rat Expression 230A Array. Gene expression data was analyzed with the Ingenuity Pathway Analysis and proprietary software. Despite more pronounced age-related vascular pathology in the F1 strain, more genes were differentially expressed in the BN strain during aging. A sample of common key genes (KLB1, TRIO, HLA-C and PCP4) showed similar expression at 6 and 15 months and downregulation at 24 months in F1 vs. upregulation in BN rats. Among the top 50 canonical pathways there was only a 10 and 30% overlap, respectively, between the F1 and BN strains in MA and TA. Most of the overexpressed molecules associated with the same vascular-related biological functions are different between strains. The data suggest that age-related vascular pathology and decrement in function is both strain and vessel-dependent and different genetic programs could be employed to accomplish both normal and pathological physiological processes in conduit and resistance arteries. two strains: two vessel types, 3 different ages
2015-03-02 | E-GEOD-55612 | biostudies-arrayexpress
Project description:NUT, nuclear protein in testis is the universal fusion partner of BRD4 in the highly aggressive NUT Midline Carcinoma (NMC), but its physiological function was unknown. Here we show that Nut is exclusively expressed in post-meiotic spermatogenic cells, at the time of genome-wide histone hyperacetylation. Inactivation of Nut induces a spermatogenesis arrest at the histone-to-protamine replacement stage, leading to male infertility. Subsequent molecular investigations show that Nut sustains global histone H4 hyperacetylation in post-meiotic cells. Additionally, Nut mediates a p300/CBP-dependent gene expression program and, by enhancing acetylation of H4 at both K5 and K8 sites, provides binding sites for the first bromodomain of Brdt, which drives histone removal. Nut’s major function is therefore to use the ubiquitous HATs p300/CBP to direct a cell-type specific histone hyperacetylation. Its ectopic activity in NMC recreates a forced p300-induced histone hyperacetylation / bromodomain binding loop that normally operates in post-meiotic spermatogenic cells.
2018-10-02 | PXD008727 | Pride
Project description:Respiratory Syncytial Virus (RSV) causes severe inflammation and airway pathology in children and the elderly by infecting the epithelial cells of the upper and lower respiratory tract. RSV replication is sensed by intracellular pattern recognition receptors upstream of the IRF and NF-$\upkappa$B transcription factors. These proteins coordinate an innate inflammatory response via Bromodomain containing protein 4 (BRD4), a protein that functions as a scaffold for unknown transcriptional regulators. To better understand the pleiotropic regulatory function of BRD4, we examine the BRD4 interactome and identify how RSV infection dynamically alters it. To accomplish these goals, we leverage native immunoprecipitation and Parallel Accumulation – Serial Fragmentation (PASEF) mass spectrometry to examine BRD4 complexes isolated from human alveolar epithelial cells in the absence or presence of RSV infection. In addition, we explore the role of BRD4's acetyl-lysine binding bromodomains in mediating these interactions by using a highly selective competitive bromodomain inhibitor. We identify 101 proteins that are significantly enriched in the BRD4 complex and are responsive to both RSV-infection and BRD4 inhibition. These proteins are highly enriched in transcription factors and transcriptional coactivators. Among them, we identify members of the AP1 transcription factor complex, a complex important in innate signaling and cell stress responses. We independently confirm the BRD4/AP1 interaction in primary human small airway epithelial cells. We conclude that BRD4 recruits multiple transcription factors during RSV infection in a manner dependent on acetyl-lysine binding domain interactions. This data suggests that BRD4 recruits transcription factors to target its RNA processing complex to regulate gene expression in innate immunity and inflammation.
2021-03-17 | PXD023983 | Pride