Project description:The mouse Ikaros-deficient thymic lymphoma cell line T29 was treated with a gamma-secretase inhibitor or vehicle (DMSO) for 36h and subjected to transcriptome analysis. 4 samples
Project description:The mouse Ikaros-deficient thymic lymphoma cell line T29 was treated with a gamma-secretase inhibitor or vehicle (DMSO) for 36h and subjected to transcriptome analysis.
Project description:T cell development is accompanied by epigenetic changes that ensure the silencing of stem cell-related, and the activation of lymphocyte-specific programs. How transcription factors influence these changes remains unclear. We show that the Ikaros transcription factor interacts with the Polycomb Repressive Complex 2 (PRC2) in CD4-CD8- thymocytes, and allows its binding to >200 developmentally-regulated genes, many of which are expressed in hematopoietic stem cells. Loss of Ikaros in CD4-CD8- cells leads to diminished histone H3 Lys27 (H3K27) trimethylation and ectopic expression of these genes. Ikaros binding triggers PRC2 recruitment and H3K27 trimethylation. Furthermore, Ikaros interacts with PRC2 independently of the Nucleosome Remodeling and Deacetylation complex. Our results identify Ikaros as a fundamental regulator of PRC2 function in developing T cells. Genome-wide comparison of different histone modifications, Ikaros, Suz12 and NuRD binding in different stages of T cell development in WT and Ikaros mutant mice. Profiling of H3K27me3 in DN1, DN2, DN3, DN4 and DP thymocytes and hematopoietic stem and progenitor cells (LSK cells) of WT and Ikaros mutant mice. Profiling of H3K4me3 and H3ac in WT and Ikaros mutant DP thymocytes. Global analysis of Ikaros binding in WT DN3, DN4 and DP cells, Suz12 binding in WT and Ikaros mutant DN3 cells, and Mta2 and Mi2beta binding in WT DN3 cells. Genome-wide profiling of Ikaros binding and H3K27me3 upon Ikaros activation in Ikaros-deficient leukemic T cells.
Project description:Lineage-negative thymocytes were cultured on OP9-DL1 stromal cells for 16h in the presence of DMSO or the gamma secretase inhibitor MRK-003. DN3 cells cells were then sorted and their transcriptome analyzed. 8 samples
Project description:Lineage-negative thymocytes were cultured on OP9-DL1 stromal cells for 16h in the presence of DMSO or the gamma secretase inhibitor MRK-003. DN3 cells cells were then sorted and their transcriptome analyzed.
Project description:This randomized phase I/II clinical trial is studying the side effects and best dose of gamma-secretase/notch signalling pathway inhibitor RO4929097 when given together with vismodegib and to see how well they work in treating patients with advanced or metastatic sarcoma. Vismodegib may slow the growth of tumor cells. Gamma-secretase/notch signalling pathway inhibitor RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving vismodegib together with gamma-secretase/notch signalling pathway inhibitor RO4929097 may be an effective treatment for sarcoma.
Project description:To address the question of whether γ-secretase deficiency affects the tonic signaling in microglia in vivo as well, we analyzed the single-cell transcriptomes of the γ-secretase deficient microglia from WT and AD mouse models at 3 ,6 and 7 months of age. Like the in vitro observations, genetic knockout of γ-secretase induced mild changes to the transcriptomes of in vivo microglia in the WT mice and also AD mice at 3 months. However, The relative proportions of DAM, CRM and TRM were significantly reduced in AppNL-G-F-GSiΔMG mice compared to AppNL-G-F-GSWT mice at 7 months, whereas HM and tCRM were significantly increased. Thus γ-secretase has a crucial role in the microglial transition from the homeostatic to the full DAM phenotype in AD.
