Dataset's files
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| HMS_LINCS&file=LDS-1120.tar.gz | Other |
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Project description:It is now established that the transcription factors E2A, EBF1 and FoxoM-BM- 1 play critical roles in B cell development. Here we show that E2A and EBF1 bound regulatory elements present in the Foxo1 locus. E2A and EBF1 as well as E2A and Foxo1, in turn, were wired together by a vast spectrum of cis-regulatory codes. These associations were dynamic during developmental progression. Occupancy by the E2A isoform, E47, directly elevated the abundance as well as the pattern of histone H3K4 monomethylation across putative enhancer regions. Finally, the pro-B cell epigenome was divided into clusters of loci that show E2A, EBF and Foxo1 occupancy. From this analysis a global network consisting of transcriptional regulators, signaling and survival factors, was constructed that we propose orchestrates the B cell fate. ChIP-Seq and gene expression profiling was performed in a variety of genetically modified primary B cell populations and cell lines approximating developmental stages of B cell development.
2010-06-12 | E-GEOD-21978 | biostudies-arrayexpress
Project description:Cyclin-Dependent Kinase 9 (CDK9) as part of the PTEFb complex promotes transcriptional elongation by promoting RNAPII pause release. We now report that, paradoxically, CDK9 is also essential for maintaining gene silencing at heterochromatic loci. Through a live cell screen, we discovered that CDK9 inhibition reactivates epigenetically silenced genes in cancer, leading to restored tumor suppressor gene expression and cell differentiation, along with activation of endogenous retrovirus (ERV) genes. CDK9 inhibition dephosphorylates the SWI/SNF protein SMARCA4 and represses HP1α expression, both of which contribute to gene reactivation. Based on gene activation, we developed the highly selective and potent CDK9 inhibitor MC180295 (IC50 =5nM) that has broad anti-cancer activity in-vitro and is effective in in-vivo cancer models. Additionally, CDK9 inhibition sensitizes with the immune checkpoint inhibitor α-PD-1 in vivo, making it an excellent target for epigenetic therapy of cancer.
2020-05-26 | PXD009573 | Pride
Project description:We investigated the potential role of AMPK in the phosphorylation of ORP8.In vitro kinase assay using purified ORP8 and kinase-active AMPK complex confirmed that ORP8 is the direct substrate of AMPK. Phosphorylated ORP8 from in vitro kinase assay was analyzed by HPLC-MS/MS.
2023-10-24 | PXD036201 | Pride
Project description:Paracoccidioidomycosis (PCM) is the cause of several deaths from systemic mycoses. The etiological agents of PCM belong to the Paracoccidioides genus, which is restricted to Latin America. The infection is acquired through inhalation of conidia that primarily lodges in the lungs and may disseminate to other organs/tissues. Treatment of PCM is commonly achieved via the administration of antifungals such as amphotericin B, co-trimoxazole, and itraconazole. The antifungal toxicity and side effects, in addition to the long treatment time, have driven research for new bioactive compounds. Argentilactone, a compound isolated from the Brazilian savanna plant Hyptis ovaliofolia, has been suggested to be a potent antifungal, inhibiting the dimorphism of P. brasiliensis and enzymatic activity of isocitrate lyase, a key enzyme of the glyoxylate cycle. Furthermore, argentilactone has no cytotoxicity and genotoxicity in fibroblast cells at concentrations that inhibit fungal growth. This work was developed due to the importance of elucidating the putative mode of action of argentilactone. The chemoproteomics approach, by affinity chromatography, is the methodology used to explore the interactions between P. brasiliensis proteins and argentilactone. A total of 109 proteins was identified and classified functionally, with those related to amino acid metabolism, energy, and detoxification being the most representative. The interactome of argentilactone binding proteins was predicted. Argentilactone inhibited the enzymatic activity of malate dehydrogenase, citrate synthase, and pyruvate dehydrogenase. Furthermore, argentilactone induced the production of reactive oxygen species. In addition, our data were compared to previously obtained proteomics and transcriptional data. Altogether, our results reveal argentilactone as a promising antifungal.
2018-02-07 | PXD008858 | Pride
Project description:The variation among induced pluripotent stem cells (iPSCs) in their differentiation capacity to specific lineages is frequently attributed to somatic memory. In this study, we compared hematopoietic differentiation capacity of 35 human iPSC lines derived from four different tissues and four embryonic stem cell lines. The analysis revealed that hematopoietic commitment capacity (PSCs to hematopoietic precursors) is correlated with the expression level of the IGF2 gene independent of the iPSC origins. In contrast, maturation capacity (hematopoietic precursors to mature blood) is affected by iPSC origin; blood-derived iPSCs showed the highest capacity. However, some fibroblast-derived iPSCs showed higher capacity than blood-derived clones. Tracking of DNA methylation changes during reprogramming reveals that maturation capacity is highly associated with aberrant DNA methylation acquired during reprogramming, rather than the types of iPSC origins. These data demonstrated that variations in the hematopoietic differentiation capacity of iPSCs are not attributable to somatic memories of their origins. Human iPSCs after hematopoietic differentiation (n = 2), human iPSCs after neural differentiation (n = 1), human iPSCs with different culture conditions (n = 8), and human iPSC line forced to express IGF2 gene (n = 1), and its control (n = 1).
2016-06-29 | E-GEOD-75096 | biostudies-arrayexpress
Project description:SCYX-7158, an oxaborole, is currently in Phase I clinical trials for the treatment of human African trypanosomiasis. Here we investigate possible modes of action against Trypanosoma brucei using a chemo-proteomic approach. SILAC-based proteomic studies using an oxaborole analogue immobilised onto a resin was used either in competition with a soluble oxaborole or an immobilised inactive control to identify thirteen proteins common to both strategies. The diverse list of binding partners from the proteomic studies suggest a degree of polypharmacology that should reduce the risk of resistance to this compound class emerging in the field.
2015-11-25 | PXD002848 | Pride
Project description:In Homo sapiens, Streptococcus agalactiae is a common colonizer of the rectovaginal tract and a fundamental cause of neonatal and non-pregnant adults infectious diseases. It also causes infectious disease in fish which compromises food safety as well as possesses a zoonotic risk. Lysine crotonylation (Kcr) is a type of histone post-translational modifications discovered in 2011. Kcr dynamics are involved in active gene promoters and potential enhancers in yeast and mammalian. However, lysine crotonylation in S. agalactiae has not yet been studied. In the present study, we conducted the first proteome-wide profiling of Kcr in S. agalactiae and identified 241 Kcr sites on 675 proteins, representing the Kcr event in S. agalactiae. Bioinformatics analysis showed that 164 sequences were matched to a total of six definitively conserved motifs, and many of them were significantly enriched in metabolic processes, cellular process, and single-organism processes. Moreover, we found four crotonylation modified proteins predicted as quorum sensing system and virulence factors, which indicate the important role of PTM on bacterial QS system and virulence. These data represent the first report of a global crotonylation proteome and provide a promising starting point for further functional research of crotonylation in bacterial virulence in S. agalactiae.
2021-12-30 | PXD026445 | Pride
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2016-06-29 | E-GEOD-60924 | biostudies-arrayexpress
Project description:The receptor tyrosine kinase EPHA2 has gained interest as therapeutical drug target in cancer and infectious diseases in the past years. However, EPHA2 research and EPHA2 based therapies have been hampered by the lack of selective small molecule EPHA2 inhibitors. We report on the synthesis and evaluation of dedicated EPHA2 inhibitors based on the clinical BCR-ABL/SRC inhibitor Dasatinib as lead structure. We designed hybrid structures of Dasatinib, CHEBI-513815, PD-173955 and a known EPHB4 inhibitor aiming at the exploitation of the ATP pocket entrance and the ribose pocket. Medicinal chemistry and inhibitor design was guided by a chemical proteomic approach allowing for early selectivity profiling of the newly synthesized inhibitor candidates. Additionally, protein crystallography delivered detailed insight into the molecular interactions that consitute structure-affinity-relationships. Finally, the anti-proliferative effect of the inhibitor candidates was confirmed in the glioblastoma cell line SF-268. In this work, we discovered a novel EPHA2 inhibitor candidate 4a comprising an improved selectivity profile while maintaining potency against EPHA2 and anti-cancer activity in SF-268 cells.
2017-05-30 | PXD006193 | Pride
Project description:Here, we provide a comprehensive overview of the selectivity profiles of 242 kinase inhibitors currently in clinical trials. We screened available inhibitors against human protein kinases by using the Kinobead technology resulting in a drug matrix identifying the druggable kinome and related proteins.
2017-12-01 | PXD005336 | Pride