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Project description:Recent sequencing efforts have failed to identify consistent oncogenic driver mutations in most adult soft tissue sarcomas. Therefore, we investigated alternate genetic/epigenetic mechanisms underlying sarcomagenesis to facilitate development of novel therapeutics. Our previous work showed that deregulation of the Hippo pathway increases proliferation in many types of sarcoma. We have now identified the mechanism of Hippo-mediated sarcomagenesis using autochthonous mouse models, ChIP-seq (H3K27Ac) and super-enhancer (SE) analysis of human undifferentiated pleomorphic sarcoma (UPS), an aggressive muscle-derived tumor. We found that the Hippo effector, Yes-Associated Protein 1 (YAP1) enhances NF-êB signaling and that YAP1 is constitutively active in these tumors due to epigenetic silencing of its inhibitor Angiomotin (AMOT). Treatment with epigenetic modulators (SAHA and JQ1) inhibited YAP1 transcription and restored expression of AMOT. These changes initiated a muscle differentiation program and reduced tumorigenesis.
2018-03-01 | GSE97296 | GEO
Project description:Recent sequencing efforts have failed to identify consistent oncogenic driver mutations in most adult soft tissue sarcomas. Therefore, we investigated alternate genetic/epigenetic mechanisms underlying sarcomagenesis to facilitate development of novel therapeutics. Our previous work showed that deregulation of the Hippo pathway increases proliferation in many types of sarcoma. We have now identified the mechanism of Hippo-mediated sarcomagenesis using autochthonous mouse models, ChIP-seq (H3K27Ac) and super-enhancer (SE) analysis of human undifferentiated pleomorphic sarcoma (UPS), an aggressive muscle-derived tumor. We found that the Hippo effector, Yes-Associated Protein 1 (YAP1) enhances NF-êB signaling and that YAP1 is constitutively active in these tumors due to epigenetic silencing of its inhibitor Angiomotin (AMOT). Treatment with epigenetic modulators (SAHA and JQ1) inhibited YAP1 transcription and restored expression of AMOT. These changes initiated a muscle differentiation program and reduced tumorigenesis.
2018-03-01 | GSE97295 | GEO
Project description:Super-enhancer analysis of human sarcomas reveals YAP1 control of NF-κB-dependent tumorigenesis
| PRJNA381219 | ENA
Project description:Proinflammatory stimuli elicit rapid transcriptional responses via transduced signals to master regulatory transcription factors. To explore the role of chromatin-dependent signal transduction in the atherogenic inflammatory response, we characterized the dynamics, structure, and function of regulatory elements in the activated endothelial cell epigenome. Stimulation with tumor necrosis factor alpha prompted a dramatic and rapid global redistribution of chromatin activators to massive de novo clustered enhancer domains. Inflammatory super enhancers formed by nuclear factor-kappa B accumulate at the expense of immediately decommissioned, basal endothelial super enhancers, despite persistent histone hyperacetylation. Mass action of enhancer factor redistribution causes momentous swings in transcriptional initiation and elongation. A chemical genetic approach reveals a requirement for BET bromodomains in communicating enhancer remodeling to RNA Polymerase II and orchestrating the transition to the inflammatory cell state, demonstrated in activated endothelium and macrophages. BET bromodomain inhibition abrogates super enhancer-mediated inflammatory transcription, atherogenic endothelial responses, and atherosclerosis in vivo.
| S-EPMC4224636 | biostudies-literature
Project description:Metastases, the spread of cancer cells to distant organs, cause the majority of cancer-related deaths. Few metastasis-specific driver mutations have been identified, suggesting aberrant gene regulation as a source of metastatic traits. However, how metastatic gene expression programs arise is poorly understood. Here, using human-derived metastasis models of renal cancer, we identify transcriptional enhancers that promote metastatic carcinoma progression. Specific enhancers and enhancer clusters are activated in metastatic cancer cell populations, and the associated gene expression patterns are predictive of poor patient outcome in clinical samples. We find that the renal cancer metastasis-associated enhancer complement consists of multiple coactivated tissue-specific enhancer modules. Specifically, we identify and functionally characterize a coregulatory enhancer cluster, activated by the renal cancer driver HIF2A and an NF-κB-driven lymphoid element, as a mediator of metastasis in vivo We conclude that oncogenic pathways can acquire metastatic phenotypes through cross-lineage co-option of physiologic epigenetic enhancer states.Significance: Renal cancer is associated with significant mortality due to metastasis. We show that in metastatic renal cancer, functionally important metastasis genes are activated via co-option of gene regulatory enhancer modules from distant developmental lineages, thus providing clues to the origins of metastatic cancer. Cancer Discov; 8(7); 850-65. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 781.
| S-EPMC6031301 | biostudies-literature
Project description:The transcription factor NF-κB, which plays an important role in cell fate determination, is involved in the activation of super-enhancers (SEs). However, the biological functions of the NF-κB SEs in gene control are not fully elucidated. We investigated the characteristics of NF-κB-mediated SE activity using fluorescence imaging of RelA, single-cell transcriptome and chromatin accessibility analyses in anti-IgM-stimulated B cells. The formation of cell stimulation-induced nuclear RelA foci was abolished in the presence of hexanediol, suggesting an underlying process of liquid-liquid phase separation. The gained SEs induced a switch-like expression and enhanced cell-to-cell variability in transcriptional response. These properties were correlated with the number of gained cis-regulatory interactions, while switch-like gene induction was associated with the number of NF-κB binding sites in SE. Our study suggests that NF-κB SEs have an important role in the transcriptional regulation of B cells possibly through liquid condensate formation consisting of macromolecular interactions.
| S-EPMC9191726 | biostudies-literature
Project description:Sirtuin-1 (SIRT1) regulates hepatic metabolism but its contribution to NF-κB-dependent inflammation has been overlooked. Cysteine cathepsins (Cathepsin B or S, CTSB/S) execute specific functions in physiological processes, such as protein degradation, having SIRT1 as a substrate. We investigated the roles of CTSB/S and SIRT1 in the regulation of hepatic inflammation using primary parenchymal and non-parenchymal hepatic cell types and cell lines. In all cells analyzed, CTSB/S inhibition reduces nuclear p65-NF-κB and κB-dependent gene expression after LPS or TNF through enhanced SIRT1 expression. Accordingly, SIRT1 silencing was sufficient to enhance inflammatory gene expression. Importantly, in a dietary mouse model of non-alcoholic steatohepatitis, or in healthy and fibrotic mice after LPS challenge, cathepsins as well as NF-κB-dependent gene expression are activated. Consistent with the prominent role of cathepsin/SIRT1, cysteine cathepsin inhibition limits NF-κB-dependent hepatic inflammation through the regulation of SIRT1 in all in vivo settings, providing a novel anti-inflammatory therapeutic target in liver disease.
| S-EPMC5260902 | biostudies-literature
Project description:Four 'protein inhibitors of activated STAT' (PIAS) control STAT-dependent and NF-κB-dependent immune signalling in humans. The genome of rainbow trout (Oncorhynchus mykiss) contains eight pias genes, which encode at least 14 different pias transcripts that are differentially expressed in a tissue- and cell-specific manner. Pias1a2 was the most strongly expressed variant among the analysed pias genes in most tissues, while pias4a2 was commonly low or absent. Since the knock-out of Pias factors in salmonid CHSE cells using CRISPR/Cas9 technology failed, three structurally different Pias protein variants were selected for overexpression studies in CHSE-214 cells. All three factors quenched the basal activity of an NF-κB promoter in a dose-dependent fashion, while the activity of an Mx promoter remained unaffected. Nevertheless, all three overexpressed Pias variants from trout strongly reduced the transcript level of the antiviral Stat-dependent mx gene in ifnγ-expressing CHSE-214 cells. Unlike mx, the overexpressed Pias factors modulated the transcript levels of NF-κB-dependent immune genes (mainly il6, il10, ifna3, and stat4) in ifnγ-expressing CHSE-214 cells in different ways. This dissimilar modulation of expression may result from the physical cooperation of the Pias proteins from trout with differential sets of interacting factors bound to distinct nuclear structures, as reflected by the differential nuclear localisation of trout Pias factors. In conclusion, this study provides evidence for the multiplication of pias genes and their sub-functionalisation during salmonid evolution.
| S-EPMC8657546 | biostudies-literature
Project description:Mutations in the core RNA splicing factor SF3B1 are prevalent in leukemias and uveal melanoma, but hotspot SF3B1 mutations are also seen in epithelial malignancies such as breast cancer. Although hotspot mutations in SF3B1 alter hematopoietic differentiation, whether SF3B1 mutations contribute to epithelial cancer development and progression is unknown. Here, we identify that SF3B1 mutations in mammary epithelial and breast cancer cells induce a recurrent pattern of aberrant splicing leading to activation of AKT and NF-κB, enhanced cell migration, and accelerated tumorigenesis. Transcriptomic analysis of human cancer specimens, MMTV-cre Sf3b1K700E/WT mice, and isogenic mutant cell lines identified hundreds of aberrant 3' splice sites (3'ss) induced by mutant SF3B1. Consistently between mouse and human tumors, mutant SF3B1 promoted aberrant splicing (dependent on aberrant branchpoints as well as pyrimidines downstream of the cryptic 3'ss) and consequent suppression of PPP2R5A and MAP3K7, critical negative regulators of AKT and NF-κB. Coordinate activation of NF-κB and AKT signaling was observed in the knockin models, leading to accelerated cell migration and tumor development in combination with mutant PIK3CA but also hypersensitizing cells to AKT kinase inhibitors. These data identify hotspot mutations in SF3B1 as an important contributor to breast tumorigenesis and reveal unique vulnerabilities in cancers harboring them.
| S-EPMC7773370 | biostudies-literature
Project description:IntroductionImproving treatments for Diffuse Large B-Cell Lymphoma (DLBCL) is challenged by the vast heterogeneity of the disease. Nuclear factor-κB (NF-κB) is frequently aberrantly activated in DLBCL. Transcriptionally active NF-κB is a dimer containing either RelA, RelB or cRel, but the variability in the composition of NF-κB between and within DLBCL cell populations is not known.ResultsHere we describe a new flow cytometry-based analysis technique termed "NF-κB fingerprinting" and demonstrate its applicability to DLBCL cell lines, DLBCL core-needle biopsy samples, and healthy donor blood samples. We find each of these cell populations has a unique NF-κB fingerprint and that widely used cell-of-origin classifications are inadequate to capture NF-κB heterogeneity in DLBCL. Computational modeling predicts that RelA is a key determinant of response to microenvironmental stimuli, and we experimentally identify substantial variability in RelA between and within ABC-DLBCL cell lines. We find that when we incorporate NF-κB fingerprints and mutational information into computational models we can predict how heterogeneous DLBCL cell populations respond to microenvironmental stimuli, and we validate these predictions experimentally.DiscussionOur results show that the composition of NF-κB is highly heterogeneous in DLBCL and predictive of how DLBCL cells will respond to microenvironmental stimuli. We find that commonly occurring mutations in the NF-κB signaling pathway reduce DLBCL's response to microenvironmental stimuli. NF-κB fingerprinting is a widely applicable analysis technique to quantify NF-κB heterogeneity in B cell malignancies that reveals functionally significant differences in NF-κB composition within and between cell populations.
| S-EPMC10272839 | biostudies-literature