Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The histone acetylation reader ENL is required for oncogenic transcription driven by super-enhancer and represents a synergistic vulnerability for BET inhibition [RNA-Seq II]

ABSTRACT: The histone acetylation reader ENL is identifed as a key factor controlling super-enhancer-driven transcription. We thus perturbed BRD4, a well-known super-enhancer regulator, protein expression with a well-validated BRD4 PROTAC (proteolysis targeting chimeric) compound dBET1 and examined whether BRD4 was required for proper function of ENL in regulation gene transcription.

ORGANISM(S): Homo sapiens

PROVIDER: GSE249552 | GEO | 2024/01/18

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

The histone acetylation reader ENL is required for oncogenic transcription driven by super-enhancer and represents a synergistic vulnerability for BET inhibition [RNA-seq]

Project description:The histone acetylation reader ENL is identifed as a key factor controlling super-enhancer-driven transcription. Therefore, we constructed a targeted degradation system of endogenous ENL protein and investigated the roles of ENL in regulating oncogenic transcription through epigenetic reprogramming.

2024-01-18 | GSE230421 | GEO

The histone acetylation reader ENL is required for oncogenic transcription driven by super-enhancer and represents a synergistic vulnerability for BET inhibition [ChIP-seq]

2024-01-18 | GSE230420 | GEO

The histone acetylation reader ENL is required for oncogenic transcription driven by super-enhancer and represents a synergistic vulnerability for BET inhibition [ChIP-Seq II]

2024-01-18 | GSE249553 | GEO

Targeting super-enhancer induced gene expression using novel BRD4 inhibitor OTX015 in preclinical models of MYCN-amplified neuroblastoma

Project description:Bromodomain-containing protein 4 (BRD4) functions as an epigenetic reader and binds to so-called super-enhancer regions of driving oncogenes such as MYC in cancer. We investigated the possibility to target super-enhancer regulated genes in neuroblastoma and in MYCN amplified disease in particular. We used OTX015, the first small-molecule BRD4 inhibitor to enter clinical phase I/II trials in adults, to test the feasibility to specifically target super-enhancer regulated gene-expression in neuroblastoma. BRD4 inhibition lead to significant transcriptional down-regulation of genes that were associated with super-enhancers, supporting the notion that BRD4 preferentially acts at these chromatin sites. BRD4 inhibition not only attenuated MYCN transcription but most significantly affected MYCN-regulated transcriptional programs.

2016-07-03 | E-MTAB-3672 | biostudies-arrayexpress

Chemical inhibition of ENL/AF9 YEATS domains in acute leukemia [RNA-Seq]

Project description:Transcriptional co-regulators, which mediate chromatin-dependent transcriptional signaling, represent tractable targets to modulate tumorigenic gene expression programs with small molecules. Genetic loss-of-function studies have recently implicated the transcriptional co-activator, ENL, as a selective requirement for the survival of acute leukemia – particularly those driven by multiple lineage leukemia (MLL)-fusion oncogenes. The YEATS domain of ENL, which binds to chromatin by interacting with acyl-lysine side chains, is critical for its pathogenic function in acute leukemiaand highlighted an essential role for its chromatin reader YEATS domain. Motivated by these recent discoveries, we executed a screen of nearly 300,000 small molecules to identify chromatin-competitiveand identified an amido-imidazopyridine inhibitors of the ENL YEATS domain (IC50 = 7 µM). Leveraging a SuFEx-based high-throughput approach to Optimizing an amido-imidazopyridine scaffold with highly parallelized, SuFEx-based medicinal chemistry optimization, we discovered SR-0813 (IC50 = 25 nM), a potent and selective ENL/AF9 YEATS domain inhibitor that exclusively inhibits the growth of ENL-dependent leukemia cell lines. Armed with this tool and a first-in-class ENL PROTAC, SR-1114, we detailed the response of AML cells to pharmacological ENL disruption for the first time. Most notably, displacement of In AML cells, SR-0813 evicts ENL from chromatin, by SR-0813 preferentially suppresseselicited a strikingly selective suppression of ENL target genes, including HOXA9/10, MYB, MYC and a number of other leukemia proto-oncogenes. Our study reproduces a number of key observations previously made by CRISPR/Cas9 loss of function and dTAG-mediated degradation, and therefore, both reinforces ENL as an emerging leukemia target and validates SR-0813 as a high-quality chemical probe.

2020-12-04 | GSE162592 | GEO

Chemical inhibition of ENL/AF9 YEATS domains in acute leukemia [ChIP-Seq]

2020-12-04 | GSE162591 | GEO

Small-molecule inhibition of the acyl-lysine reader ENL as a strategy against acute myeloid leukemia [ChIP-Seq]

Project description:Acute myeloid leukemia (AML) is characterized by dysregulated transcriptional programs and these programs require support from chromatin regulators to maintain their hyperactive state. Recent studies have identified the histone acylation ‘reader’ ENL as being a critical dependency in AML, but the potential of therapeutic applications targeting this chromatin reader remains poorly understood. Here, we present a potent and orally bioavailable small-molecule inhibitor of ENL, TDI-055, which displaces ENL from chromatin by competitively blocking the interaction of its YEATS domain with acylated histones. We show that TDI-055 treatment preferentially inhibited the proliferation of human leukemia cells harboring MLL translocations or NPM1 mutations. Through a CRISPR/Cas9 saturated mutagenesis screen, we uncovered an ENL mutant that could confer cells resistance to TDI-055, thus providing compelling proof for the on-target activity of the compound. Rapid displacement of ENL from chromatin resulted in decreased recruitment of select ENL-associated complexes and impaired RNA polymerase II elongation which, in turn, led to the suppression of critical leukemogenic gene expression programs. Finally, pharmacological inhibition of ENL in vivo led to reduced AML growth and prolonged survival in cell line and patient-derived xenograft (PDX) models. Collectively, these results provide critical evidence and mechanistic insights to establish inhibition of ENL as a potential therapeutic strategy against molecularly defined AML, laying the foundation for rapid clinical translation of this approach.

2022-10-05 | GSE185093 | GEO

Small-molecule inhibition of the acyl-lysine reader ENL as a strategy against acute myeloid leukemia [RNA-Seq]

2022-10-05 | GSE185091 | GEO

ChIP-seq for the identification of enhancer and super enhancers in Acute Myeloid Leukemia cells with a 3q-aberration

Project description:To infer enhancers and super enhancers in Acute Myeloid Leukemia (AML) Cell lines with a 3q-aberration we determined regions enriched for H3K27AC, H3K4ME3, H3K4ME1, P300, and BRD4 in MOLM1. Additionally we determined regions enriched for P300 and BRD4 in the cell line Mutz3 which also harbors a 3q-aberration. As an control we performed Chip-Seq to determine enrichment for BRD4 in K562, which overexpresses the proto-oncogene EVI1, but has no apparent 3q-aberration. Ultimately, the ChipSeq experiments were utilized to infer which enhancer or super enhancer drives the overexpression of EVI1 in AMLs with a 3q-aberration. Finally, the effect of the compound JQ1 on the inferred super enhancers and the overexpression of EVI1 is tested by treating the cell line MOLM1 for 6 hours and determining the residual binding of BRD4.

2014-04-03 | E-MTAB-2224 | biostudies-arrayexpress

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

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data