Similar Datasets
Project description:Chromatin regulators are frequently mutated in human cancer and are attractive drug targets. They include diverse proteins that share functional domains and assemble into related multi-subunit complexes. To investigate functional relationships among these regulators, here we apply combinatorial CRISPR knockouts (KOs) to test over 35,000 gene-gene pairings in leukemia cells, using a library of over 300,000 constructs. Top pairs that demonstrate either compensatory non-lethal interactions or synergistic lethality enrich for paralogs and targets that occupy the same protein complex. The screen highlights protein complex dependencies not apparent in single KO screens, for example MCM histone exchange, the nucleosome remodeling and deacetylase (NuRD) complex, and HBO1 (KAT7) complex. We explore two approaches to NuRD complex inactivation. Paralog and non-paralog combinations of the KAT7 complex emerge as synergistic lethal and specifically nominate the ING5 PHD domain as a potential therapeutic target when paired with other KAT7 complex member losses. These findings highlight the power of combinatorial screening to provide mechanistic insight and identify therapeutic targets within redundant networks.
2022-12-16 | GSE215348 | GEO
Project description:Combinatorial CRISPRko screening data in leukemia cell lines
2022-12-16 | GSE215347 | GEO
Project description:Combinatorial CRISPRko screening data in leukemia cell lines
2022-12-16 | GSE215346 | GEO
Project description:Molecular functions of the Nucleosome Remodeling and Deacetylation (NuRD) complex in the control of gene expression were investigated using an inducible system to direct its assembly in embryonic stem cells. This dataset maps time-resolved DNA association of NuRD complex members, pluripotency factors, components of the RNA polymerase II machinery and changes to histone modifications.
2018-05-31 | E-MTAB-6804 | biostudies-arrayexpress
Project description:In the developing subpallium, the fate decision between neurons and glia is driven by expression of Dlx1/2 or Olig1/2 respectively, two sets of transcription factors (TFs) with a mutually repressive relationship. The mechanism by which Dlx1/2 repress progenitor and oligodendrocyte fate, while promoting transcription of genes needed for differentiation, is not fully understood. We identified a motif within DLX1 that binds RBBP4, a NuRD complex subunit. ChIP-seq studies of genomic occupancy of DLX1 and six different members of the NuRD complex show that DLX1 and NuRD colocalize to putative regulatory elements (pREs) enriched near other transcription factor genes. Loss of Dlx1/2 leads to dysregulation of genome accessibility at pREs near genes repressed by Dlx1/2, including Olig2. Consequently, heterozygosity of Dlx1/2 and Rbbp4 leads to an increase in the production of OLIG2+ cells. These findings highlight the importance of the interplay between TFs and chromatin remodelers in regulating cell fate decisions.
2022-06-01 | GSE194076 | GEO
Project description:Molecular functions of the Nucleosome Remodeling and Deacetylation (NuRD) complex in the control of gene expression were investigated using an inducible system to direct its assembly in embryonic stem cells. This dataset profiles nascent RNA transcription in response to NuRD induction.
2018-05-31 | E-MTAB-6805 | biostudies-arrayexpress
Project description:Purpose of reviewIn an attempt to identify potential new therapeutic targets, efforts to describe the metabolic features unique to cancer cells are increasingly being reported. Although current standard of care regimens for several pediatric malignancies incorporate agents that target tumor metabolism, these drugs have been part of the therapeutic landscape for decades. More recent research has focused on the identification and targeting of new metabolic vulnerabilities in pediatric cancers. The purpose of this review is to describe the most recent translational findings in the metabolic targeting of pediatric malignancies.Recent findingsAcross multiple pediatric cancer types, dependencies on a number of key metabolic pathways have emerged through study of patient tissue samples and preclinical modeling. Among the potentially targetable vulnerabilities are glucose metabolism via glycolysis, oxidative phosphorylation, amino acid and polyamine metabolism, and NAD metabolism. Although few agents have yet to move forward into clinical trials for pediatric cancer patients, the robust and promising preclinical data that have been generated suggest that future clinical trials should rationally test metabolically targeted agents for relevant disease populations.SummaryRecent advances in our understanding of the metabolic dependencies of pediatric cancers represent a source of potential new therapeutic opportunities for these diseases.
| S-EPMC7263318 | biostudies-literature
Project description:Molecular functions of the Nucleosome Remodeling and Deacetylation (NuRD) complex in the control of gene expression were investigated using an inducible system to direct its assembly in embryonic stem cells. This dataset profiles time-resolved transcriptional changes in response to NuRD induction.
2018-05-31 | E-MTAB-6806 | biostudies-arrayexpress
Project description:Transcriptional coregulators have been widely pursued as targets for disrupting oncogenic gene regulatory programs. However, many proteins in this target class are universally essential for cell survival, which may limit the therapeutic window that can be achieved by drug candidates. By examining large collections of CRISPR/Cas9-based essentiality screens, we discovered a genetic interaction between histone deacetylase 1 (HDAC1) and HDAC2 wherein each paralog is synthetically lethal with hemizygous deletion of the other. This collateral synthetic lethality is caused by recurrent chromosomal translocations that occur in diverse solid and hematological malignancies, including neuroblastoma and lymphoid malignancies. Using genetic deletion or dTAG-mediated degradation, we show that HDAC2 disruption suppresses the growth of HDAC1-deficient neuroblastoma in vitro and in vivo. Mechanistically, we find that targeted degradation of HDAC2 in these cells prompts the turnover of several members of the nucleosome remodeling and deacetylase (NuRD) complex, leading to diminished chromatin accessibility at HDAC2/NuRD-bound sites of the genome and impaired control of enhancer-associated transcription. Several of the degraded NuRD complex subunits are themselves lineage-specific cancer dependencies, providing motivation to develop paralog-selective HDAC degraders. Altogether, we identify HDAC1/2 collateral synthetic lethality as a new therapeutic target and reveal a novel mechanism for exploiting NuRD-associated cancer dependencies.
2022-06-09 | GSE202703 | GEO
Project description:Molecular functions of the Nucleosome Remodeling and Deacetylation (NuRD) complex in the control of gene expression were investigated using an inducible system to direct its assembly in embryonic stem cells. This dataset identifies genome-wide changes in nucleosome positioning at sites of NuRD association.
2018-05-31 | E-MTAB-6807 | biostudies-arrayexpress