Stretch-Enhancers Delineate Disease-Associated Regulatory Nodes in T Cells
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE60482 | GEO | 2015/02/18
SECONDARY ACCESSION(S): PRJNA258386
REPOSITORIES: GEO
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Project description:T Cell stretch-enhancers are vulnerable to Jak inhibitor tofacitinib Treatment of T cells with the Janus kinase (JAK) inhibitor, tofacitinib, disproportionately altered the expression of RA risk genes with stretech-enhancer (SE) structures.
2015-02-18 | E-GEOD-60482 | biostudies-arrayexpress
Project description:Stretch-Enhancers Delineate Disease-Associated Regulatory Nodes in T Cells
| PRJNA258386 | ENA
Project description:Enhancers regulate spatiotemporal gene expression and impart cell-specific transcriptional outputs that drive cell identity. Super-enhancers (SEs), also known as stretch-enhancers, are a subset of enhancers especially important for genes associated with cell identity and genetic risk of disease. CD4(+) T cells are critical for host defence and autoimmunity. Here we analysed maps of mouse T-cell SEs as a non-biased means of identifying key regulatory nodes involved in cell specification. We found that cytokines and cytokine receptors were the dominant class of genes exhibiting SE architecture in T cells. Nonetheless, the locus encoding Bach2, a key negative regulator of effector differentiation, emerged as the most prominent T-cell SE, revealing a network in which SE-associated genes critical for T-cell biology are repressed by BACH2. Disease-associated single-nucleotide polymorphisms for immune-mediated disorders, including rheumatoid arthritis, were highly enriched for T-cell SEs versus typical enhancers or SEs in other cell lineages. Intriguingly, treatment of T cells with the Janus kinase (JAK) inhibitor tofacitinib disproportionately altered the expression of rheumatoid arthritis risk genes with SE structures. Together, these results indicate that genes with SE architecture in T cells encompass a variety of cytokines and cytokine receptors but are controlled by a 'guardian' transcription factor, itself endowed with an SE. Thus, enumeration of SEs allows the unbiased determination of key regulatory nodes in T cells, which are preferentially modulated by pharmacological intervention.
| S-EPMC4409450 | biostudies-literature
Project description:The myeloma bone marrow microenvironment drives proliferation of malignant plasma cells and promotes resistance to therapy. Interleukin-6 (IL-6) and downstream JAK/STAT signaling are thought to be central components of these microenvironment-induced phenotypes. In a prior drug repurposing screen, we identified tofacitinib, a pan-JAK inhibitor FDA-approved for rheumatoid arthritis, as an agent that may reverse the tumor-stimulating effects of bone marrow mesenchymal stromal cells.Here, we validated both in vitro, in stromal-responsive human myeloma cell lines, and in vivo, in orthotopic disseminated murine xenograft models of myeloma, that tofacitinib showed both single-agent and combination therapeutic efficacy in myeloma models. Surprisingly, we found that ruxolitinib, an FDA-approved agent targeting JAK1 and JAK2, did not lead to the same anti-myeloma effects. Combination with a novel irreversible JAK3-selective inhibitor also did not rescue ruxolitinib effects. RNA-seq and unbiased phosphoproteomics revealed that marrow stromal cells drive a JAK/STAT-mediated proliferative program in myeloma plasma cells, and tofacitinib reversed the large majority of these pro-growth signals. Taken together, our results suggest that tofacitinib specifically reverses the growth-promoting effects of the tumor microenvironment through blocking an IL-6-mediated signaling axis. As tofacitinib is already FDA-approved, these results can be rapidly translated into potential clinical benefits for myeloma patients.
2018-10-24 | PXD006581 | Pride
Project description:The goal of this study was to examine the effect of the major axis of biaxial mechanical stretch on cardiac myocyte gene expression and to identify the signaling pathways and transcription factors regulating these changes. Neonatal cardiac myocytes were cultured on a micropatterned substrate, and the primary stretch axis was applied either parallel or transverse to the myofibril direction. RNA sequencing was conducted to study whole genomic expression changes after acute cardiac myocyte stretch. The results showed a more robust gene response to longitudinal than to transverse stretch. After 30 minutes of stretch, 53 and 168 genes were considered differentially expressed (DE) from transverse and longitudinal stretch, respectively. After 4 hours, the number of DE genes increased to 795 in longitudinal stretch while it decreased to 35 in transverse stretch. Gene ontology term (GO) analysis indicated enrichment of TF activity and protein kinase activity by both stretch axes; whereas longitudinal but not transverse stretch caused expression of genes involved in sarcomere organization and cytoskeletal protein binding.
2019-06-01 | GSE83655 | GEO
Project description:Chromatin-based functional genomic analyses and genomewide association studies (GWASs) together implicate enhancers as critical elements influencing gene expression and risk for common diseases. Here, we performed systematic chromatin and transcriptome profiling in human pancreatic islets. Integrated analysis of islet data with those generated by the ENCODE project in nine cell types identified specific and significant enrichment of type 2 diabetes and related quantitative trait GWAS variants in islet enhancers. Our integrated chromatin maps reveal that most enhancers are short (median = 0.8 kb). Each cell type also contains a substantial number of more extended (?3 kb) enhancers. Interestingly, these stretch enhancers are often tissue-specific and overlap locus control regions, suggesting that they are important chromatin regulatory beacons. Indeed, we show that (i) tissue specificity of enhancers and nearby gene expression increase with enhancer length; (ii) neighborhoods containing stretch enhancers are enriched for important cell type-specific genes; and (iii) GWAS variants associated with traits relevant to a particular cell type are more enriched in stretch enhancers compared with short enhancers. Reporter constructs containing stretch enhancer sequences exhibited tissue-specific activity in cell culture experiments and in transgenic mice. These results suggest that stretch enhancers are critical chromatin elements for coordinating cell type-specific regulatory programs and that sequence variation in stretch enhancers affects risk of major common human diseases. Integrated analysis of islet chromatin modification and transcriptome data with those generated by the ENCODE project. NISC Comparative Sequencing Program
2013-11-08 | E-GEOD-51310 | biostudies-arrayexpress
Project description:Chromatin-based functional genomic analyses and genomewide association studies (GWASs) together implicate enhancers as critical elements influencing gene expression and risk for common diseases. Here, we performed systematic chromatin and transcriptome pro- filing in human pancreatic islets. Integrated analysis of islet data with those generated by the ENCODE project in nine cell types identified specific and significant enrichment of type 2 diabetes and related quantitative trait GWAS variants in islet enhancers. Our integrated chromatin maps reveal that most enhancers are short (median = 0.8 kb). Each cell type also contains a substantial number of more extended (≥3 kb) enhancers. Interestingly, these stretch enhancers are often tissue-specific and overlap locus control regions, suggesting that they are important chromatin regulatory beacons. Indeed, we show that (i) tissue specificity of enhancers and nearby gene expression increase with enhancer length; (ii) neighborhoods containing stretch enhancers are enriched for important cell type– specific genes; and (iii) GWAS variants associated with traits rele- vant to a particular cell type are more enriched in stretch enhancers compared with short enhancers. Reporter constructs containing stretch enhancer sequences exhibited tissue-specific activity in cell culture experiments and in transgenic mice. These results suggest that stretch enhancers are critical chromatin elements for coordinating cell type–specific regulatory programs and that sequence variation in stretch enhancers affects risk of major common human diseases. Integrated analysis of islet chromatin modification and transcriptome data with those generated by the ENCODE project. NISC Comparative Sequencing Program
2013-11-08 | E-GEOD-51311 | biostudies-arrayexpress
Project description:JAK inhibitors like tofacitinib were thought to act primarily on T cells. However, our data and recent research suggest that JAK receptors are also present on keratinocytes. Here, we show effect of tofacitinib on primary keratinocytes, which could explain effects of topical tofacitinib treatment in psoriasis. We have performed whole transcriptome analysis (using microarray) on RNA isolated from cultured primary keratinocytes treated either with IL-22 alone or combination of tofacitinb and IL-22 at 6 hours
2017-10-03 | GSE104509 | GEO
Project description:We profiled the transcriptomes of 4 human lung cell types that were subjected to control (non-stretch) and 30% tonic stretch conditions for 4 hours and 24 hours.
2016-04-12 | GSE80161 | GEO
Project description:We profiled the transcriptomes of 4 human lung cell types that were subjected to control (non-stretch) and 30% tonic stretch conditions for 4 hours and 24 hours. Total RNA extracted from cells under control (time-matched) or 30% stretch conditions (4 hours or 24 hours) performed in technical replicate experiments. human lung alveolar A549 cells, human lung bronchoepithelial 16HBE14o- cells, human fetal lung fibroblasts CCL-153, human juvenile lung fibroblasts CCL-151
2016-04-12 | E-GEOD-80161 | biostudies-arrayexpress