Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA261972 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR1585281.fastq.gz | Fastqsanger.gz | |||
| SRR1585282.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 2 of 2 |
Similar Datasets
Project description:High-Throughput Screen Identifies Non-Inflammatory Small Molecule Inducers of Trained Immunity
| PRJNA1127561 | ENA
Project description:Mutations in chromatin-modifying proteins and transcription factors are commonly associated with a wide variety of cancers. Through gain- or loss-of-function, these mutations may result in characteristic alterations of accessible chromatin, indicative of shifts in the landscape of regulatory elements genome-wide. The identification of compounds that reverse a specific chromatin signature could lead to chemical probes or potential therapies. To explore whether chromatin accessibility could serve as a platform for small molecule screening, we adapted formaldehyde-assisted isolation of regulatory elements (FAIRE), a chemical method to enrich for nucleosome-depleted genomic regions, as a high-throughput, automated assay. After demonstrating the validity and robustness of this approach, we applied this method to screen an epigenetically targeted small molecule library by evaluating regions of aberrant nucleosome depletion mediated by EWSR1-FLI1, the chimeric transcription factor critical for the bone and soft tissue tumor Ewing sarcoma. As a class, histone deacetylase inhibitors were greatly overrepresented among active compounds. These compounds resulted in diminished accessibility at targeted sites by disrupting transcription of EWSR1-FLI1. Capitalizing on precise differences in chromatin accessibility for drug discovery efforts offers significant advantages because it does not depend on the a priori selection of a single molecular target and may detect novel biologically relevant pathways.
2015-09-24 | GSE61735 | GEO
Project description:Mutations in chromatin modifying proteins are associated with a variety of cancers. These mutations may result in characteristic patterns of accessible chromatin indicative of altered nucleosome positioning and depletion at regulatory elements. We describe the adaptation of Formaldehyde-Assisted Isolation of Regulatory Elements (FAIRE), a chemical method to enrich for nucleosome-depleted genomic regions, as a high-throughput, automated assay. We applied this method in a screen of epigenetically targeted small molecules by evaluating regions of aberrant nucleosome depletion mediated by EWS-FLI1, the chimeric transcription factor critical for the bone and soft tissue tumor Ewing Sarcoma. We identified a novel compound, UNC0621, which exhibited a dose-dependent reduction in chromatin accessibility, decreased Ewing Sarcoma cell viability, and inhibited anchorage-independent growth. We demonstrate that chromatin accessibility can be exploited for drug discovery efforts offering the advantage that it does not depend on the a priori selection of a single molecular target. Identified compounds can then be used for biological target discovery and potential therapeutic validation. HT-FAIRE was performed on Human Umbilical Vein Endothelial Cells (HUVEC) in duplicate. No reference/control experiment is necessary.
2015-09-24 | E-GEOD-61735 | biostudies-arrayexpress
Project description:Cancer genotyping projects have identified frequent mutations in epigenetic regulators. Ewing sarcoma is a pediatric tumor characterized by the critical translocation-associated fusion oncoprotein EWS::FLI and a low mutational burden. EWS::FLI targets characteristic genetic loci where it mediates aberrant chromatin and the establishment of de novo enhancers. Ewing sarcoma thus provides a model to interrogate mechanisms underlying chromatin dysregulation in tumorigenesis. Previously, we developed a high-throughput chromatin-based screening platform and demonstrated its utility in identifying small molecules capable of altering chromatin accessibility at EWS::FLI-bound loci. Here, we report the identification of UNC0621, a molecule with previously uncharacterized mechanism of action, as a small molecule modulator of chromatin state at sites of aberrant chromatin accessibility at EWS::FLI-bound loci. UNC0621 suppresses cellular proliferation of Ewing sarcoma cell lines by cell cycle arrest. Proteomic studies demonstrate that UNC0621 associates with RNA binding and splicing proteins as well as chromatin regulatory proteins. Surprisingly, interactions with chromatin and many RNA-binding proteins, including EWS::FLI fusion protein and its known interactors, were RNA-independent. Our findings suggest that UNC0621 affects EWS::FLI-mediated chromatin activity by interacting with and altering the activity of RNA splicing machinery and chromatin modulating factors. Genetic modulation of these proteins similarly inhibits proliferation and alters chromatin in Ewing sarcoma cells. The use of an oncogene-associated chromatin signature as a target represents a novel strategy to directly screen for modulators of epigenetic machinery and provides a framework for using chromatin-based assays for future therapeutic discovery efforts.
2023-03-13 | GSE213545 | GEO
Project description:A high-throughput small molecule screen identifies synergism between DNA methylation and Aurora kinase pathways for X-chromosome reactivation
| PRJNA336175 | ENA
Project description:Cellular active small molecule inhibitors of Mycobacterium tuberculosis by NMR fragment screen.
2015-01-01 | GSE17424 | GEO
Project description:Disruption of alternative splicing frequently causes or contributes to human diseases and disorders. Consequently, there is a need for efficient and sensitive reporter assays capable of screening chemical libraries for compounds with efficacy in modulating important splicing events. Here, we describe a screening workflow employing dual Nano and Firefly luciferase alternative splicing reporters that affords highly efficient, sensitive, and linear detection of small molecule responses. Applying this system to a screen of ~95,000 small molecules, we identify compounds that selectively activate or repress a neuronal microexon network that is frequently disrupted in autism and overexpressed in neuroendocrine cancers. Remarkably, among the most potent and selective activating compounds are histone deacetylase (HDAC) inhibitors. We thus describe a high-throughput screening system for candidate splicing therapeutics, a resource of small molecule modulators of microexons, and insight into the mode of action and potential utility of HDAC inhibitors in the context of neurological disorders.
2024-05-28 | GSE228599 | GEO
Project description:We profiled chromatin accessibility across the genome of HSPCs treated with either a small molecule inhibitor of G9a/GLP or DMSO. We observed that chromatin accessibility is dramatically altered at the regions of H3K9me2 nucleation. We have characterized the regions of H3K9me2 nucleation, revealing that H3K9me2 is nucleated in HSPCs at CpG islands (CGIs) and CGI-like sequences across the genome. Our analysis furthermore revealed a bias of H3K9me2 nucleation towards regions with low rates of C->T deamination, which typically lack DNA methylation. Lastly we examined the interaction of H3K9me2 and DNA methylation and determined that chromatin accessibility changes upon loss of H3K9me2 are dependent on the presence of DNA methylation. Examination of chromatin remodeling with FAIRE-seq in HSPCs treated with either a small molecule inhibitor of G9a/GLP or DMSO
2014-09-25 | E-GEOD-59749 | biostudies-arrayexpress
Project description:The transcription factor FOXM1 binds to sequence-specific motifs on DNA (C/TAAACA) through its DNA binding domain (DBD), and activates proliferation- and differentiation-associated genes. Aberrant overexpression of FOXM1 is a key feature in oncogenesis and progression of many human cancers. Herein we identify novel inhibitors of FOXM1 that block DNA binding from a high-throughput screen applied to a library of 54,211 small molecules. One compound, FDI-6 (NCGC00099374) is studied in depth and is shown to bind directly to FOXM1 protein, displace the transcription factor from genomic targets in MCF-7 breast cancer cells, and induce concomitant transcriptional down-regulation. Global transcript profiling of MCF-7 cells by RNA-seq shows that FDI-6 specifically down regulates FOXM1-activated genes with FOXM1 occupancy confirmed by ChIP-seq. This small molecule mediated effect is selective for FOXM1-controlled genes with no effect on genes regulated by homologous forkhead family factors.
2014-08-15 | GSE58626 | GEO
Project description:High throughput screen identifies novel small molecules that derepress genes repressed by DNA methylation
| PRJNA417267 | ENA