Largimycin cluster
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ABSTRACT:
PROVIDER: PRJEB30369 | ENA |
REPOSITORIES: ENA
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Project description:A Single Cell Analysis of Myogenic Dedifferentiation Induced by Small Molecules An important direction in chemical biology is the derivation of compounds that affect cellular differentiation or its reversal. The fragmentation of multinucleate myofibers into viable mononucleates (called cellularisation) occurs during limb regeneration in urodele amphibians and the isolation of myoseverin, a tri-substituted purine that could apparently activate this pathway of myogenic dedifferentiation in mammalian cells, generated considerable interest. We have explored the mechanism and outcome of cellularisation at a single cell level, and report findings that significantly extend the previous work with myoseverin. Using a panel of compounds, including a novel triazine compound called 109 with structural similarity and comparable activity to myoseverin, we have identified microtubule disruption as critical for activation of the response. Our analysis has included the related control triazine compound 401, and the microtubule disrupting agent nocodazole. Time-lapse microscopy has enabled us to analyse the fate of identified mononucleate progeny, and directly assess the extent of dedifferentiation.
2005-08-20 | E-MEXP-401 | biostudies-arrayexpress
Project description:Mammalian zygotic genome activation (ZGA) following fertilization refers to the process that results in transcriptional awakening of the embryonic genome at two-cell (2C) stage in mice or 4-8 cell stage in human. ZGA confers to the mouse 2C embryo a unique transcriptional profile characterized by transient up-regulation of many totipotency-related genes and MERVL transposons. Intriguingly, many ZGA-related totipotent genes are duplicated and clustered in the genome during evolution, including Dux cluster, OBOX and Zscan4 family members in mice. Yet, the contribution and biological significance of the totipotency-related gene duplication events during evolution in totipotency acquisition remain poorly understood. Here, we focus on Dux cluster, the master regulator of ZGA that is necessary and sufficient for the emergence of 2C-like cells (2CLCs) and activation of target totipotent genes in mouse embryonic stem cells (ESCs). By reducing Dux gene copy number from 31 to 0 or 1 with CRISPR-Cas9 technology, we generated Dux-KO and Dux (n=1) ES cell lines, respectively. We found that the totipotent gene transcriptional profile could not be fully activated in Dux (n=1) mESCs compared to wild type (WT) mESCs after treatment with DNMT1 protein degrader, mimicking the DNA demethylation process during early embryo development. These data demonstrate that Dux cluster duplication is essential for fully activation of totipotency-related genes, ensuring ZGA and totipotency acquisition.
2024-10-12 | GSE263217 | GEO
Project description:Post-translational modifications of histones determines cell lineage- or signal-specific gene expression. Depending on the type and combination of modifications, histones bind to functionally distinct effector proteins ('readers') that control gene activation or silencing. The current pharmacological modulation of the epigenome aims to control gene expression by regulation of the enzymes that catalyze post-translational histone modifications. Here we present a novel pharmacological approach that targets gene expression by interfering with the function of histone ?readers?. We describe the impact of a synthetic compound that selectively occupies the acetylated histone-binding pocket of the Bromodomain and Extra Terminal domain (BET) family of proteins and prevents their interaction with acetylated histones. The bromodomain blocking compound suppresses the expression of a specific subset of key inflammatory genes in activated macrophages and confers protection against LPS-induced septic shock in vivo. Our findings suggest that small molecules specifically targeting histone 'readers' can serve as a new generation of drugs to treat immune diseases. Microarray, ChIP-qPCR and ChIP-seq examination of control, 1H LPS stimulated bone-marrow-derived macrophages in the presence/absence of acetylated histone mimic in mouse.
2010-11-10 | E-GEOD-21910 | biostudies-arrayexpress
Project description:The SWI/SNF complex was the first chromatin remodeling machinery discovered. Although it has been extensively investigated, numerous aspects of its regulation and activity are still poorly understood, especially in higher eukaryotes. In mammals, there is not a single SWI/SNF complex (also called BRM or BRG1 associated factors, BAF, complex) but rather a polymorphic family of complexes, with three main subtypes called canonical BAF (cBAF), polybromo-associated BAF (PBAF), and non-canonical BAF (ncBAF), with relatively different specificities. The enzymatic motors of the complexes are two mutually exclusive ATPases of the SNF2 family called BRAHMA (BRM, also called SMARCA2) and BRAHMA RELATED GENE 1 (BRG1, also called SMARCA4). Recently, an specific inhibitor of BRM and BRG1 ATPase activity, called BRM014, has been developed. We have extensively investigated the effect of BRM014 on the transcriptome and the chromatin landscape of non-tumoral normal murine mammary (NMuMG) epithelial cells.
2024-03-08 | GSE249211 | GEO
Project description:The SWI/SNF complex was the first chromatin remodeling machinery discovered. Although it has been extensively investigated, numerous aspects of its regulation and activity are still poorly understood, especially in higher eukaryotes. In mammals, there is not a single SWI/SNF complex (also called BRM or BRG1 associated factors, BAF, complex) but rather a polymorphic family of complexes, with three main subtypes called canonical BAF (cBAF), polybromo-associated BAF (PBAF), and non-canonical BAF (ncBAF), with relatively different specificities. The enzymatic motors of the complexes are two mutually exclusive ATPases of the SNF2 family called BRAHMA (BRM, also called SMARCA2) and BRAHMA RELATED GENE 1 (BRG1, also called SMARCA4). Recently, an specific inhibitor of BRM and BRG1 ATPase activity, called BRM014, has been developed. We have extensively investigated the effect of BRM014 on the transcriptome and the chromatin landscape of non-tumoral normal murine mammary (NMuMG) epithelial cells.
2024-03-08 | GSE226950 | GEO
Project description:The SWI/SNF complex was the first chromatin remodeling machinery discovered. Although it has been extensively investigated, numerous aspects of its regulation and activity are still poorly understood, especially in higher eukaryotes. In mammals, there is not a single SWI/SNF complex (also called BRM or BRG1 associated factors, BAF, complex) but rather a polymorphic family of complexes, with three main subtypes called canonical BAF (cBAF), polybromo-associated BAF (PBAF), and non-canonical BAF (ncBAF), with relatively different specificities. The enzymatic motors of the complexes are two mutually exclusive ATPases of the SNF2 family called BRAHMA (BRM, also called SMARCA2) and BRAHMA RELATED GENE 1 (BRG1, also called SMARCA4). Recently, an specific inhibitor of BRM and BRG1 ATPase activity, called BRM014, has been developed. We have extensively investigated the effect of BRM014 on the transcriptome and the chromatin landscape of non-tumoral normal murine mammary (NMuMG) epithelial cells.
2024-03-08 | GSE226949 | GEO
Project description:The SWI/SNF complex was the first chromatin remodeling machinery discovered. Although it has been extensively investigated, numerous aspects of its regulation and activity are still poorly understood, especially in higher eukaryotes. In mammals, there is not a single SWI/SNF complex (also called BRM or BRG1 associated factors, BAF, complex) but rather a polymorphic family of complexes, with three main subtypes called canonical BAF (cBAF), polybromo-associated BAF (PBAF), and non-canonical BAF (ncBAF), with relatively different specificities. The enzymatic motors of the complexes are two mutually exclusive ATPases of the SNF2 family called BRAHMA (BRM, also called SMARCA2) and BRAHMA RELATED GENE 1 (BRG1, also called SMARCA4). Recently, an specific inhibitor of BRM and BRG1 ATPase activity, called BRM014, has been developed. We have extensively investigated the effect of BRM014 on the transcriptome and the chromatin landscape of non-tumoral normal murine mammary (NMuMG) epithelial cells.
2024-03-08 | GSE226945 | GEO
Project description:The SWI/SNF complex was the first chromatin remodeling machinery discovered. Although it has been extensively investigated, numerous aspects of its regulation and activity are still poorly understood, especially in higher eukaryotes. In mammals, there is not a single SWI/SNF complex (also called BRM or BRG1 associated factors, BAF, complex) but rather a polymorphic family of complexes, with three main subtypes called canonical BAF (cBAF), polybromo-associated BAF (PBAF), and non-canonical BAF (ncBAF), with relatively different specificities. The enzymatic motors of the complexes are two mutually exclusive ATPases of the SNF2 family called BRAHMA (BRM, also called SMARCA2) and BRAHMA RELATED GENE 1 (BRG1, also called SMARCA4). Recently, an specific inhibitor of BRM and BRG1 ATPase activity, called BRM014, has been developed. We have extensively investigated the effect of BRM014 on the transcriptome and the chromatin landscape of non-tumoral normal murine mammary (NMuMG) epithelial cells.
2024-03-08 | GSE226944 | GEO
Project description:The compound (O4I3) showed a remarkable OCT4 induction, which at least in part, is due to the inhibition of H3K4-specific lysine demethylase (KDM5, also known as JARID1). Experiments demonstrated that KDM5A, serves as a reprogramming barrier via interference with the enrichment of H3K4Me3 at the OCT4 promoter. Thus, our results introduce a new class of KDM5 chemical inhibitors and provide further insight into the pluripotency-related properties of KDM5-family members.
2018-12-12 | GSE123668 | GEO
Project description:Small GTPase proteins usually serve as molecular switches in various biological process, such as the proliferation, survival, and migration of cells. Mutations or aberrant activations of small GTPase proteins, such as Ras, are frequently observed in various kinds of cancers. Drug discovery efforts that target the Ras family proteins are making breakthroughs, while the discovery of efficient inhibitors that target the Rho family proteins is still stagnant. Protein members from the Rho family, such as RhoA and Cdc42, are key regulators of the migration and invasion of cancer cells. Thus inhibitors of the Rho family proteins are promising to become drug candidates that target cancer metastasis, which is a principal cause of cancer recurrence and chemotherapy failure. Here we show the discovery and characterization of a novel covalent inhibitor named DC-RC-063 that targets the Rho family proteins, using a combined approach of computations and experiments. Revealed by solved crystal structures, compound DC-RC-063 inhibited the activation of RhoA, by disrupting protein-protein interactions, in an allosteric manner. As compound DC-RC-063 inhibited the migration and invasion of breast cancer MDA-MB-231 cells, our findings proved that the Rho family proteins are targetable for covalent inhibitors via an allosteric mechanism. The novel binding site revealed by this inhibitor can be exploited for further development of anti-cancer drugs that target cancer metastasis.
2017-12-07 | GSE106605 | GEO