An inter-chromosomal transcription hub activates the unfolded protein response in plasma cells
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PROVIDER: PRJNA449748 | ENA |
REPOSITORIES: ENA
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Project description:Previous studies have indicated that the transcription signature of antibody-secreting cells is closely associated with the induction of the unfolded protein response pathway (UPR). Here we have used genome-wide and single cell analyses to examine the folding patterns of plasma cell genomes. We found that plasma cells adopt a cartwheel configuration and undergo large-scale changes in chromatin folding at genomic regions associated with a plasma cell specific transcription signature. During plasma cell differentiation, Blimp1 assembles into an inter-chromosomal transcription hub with genes associated with the UPR, biosynthesis of the endoplasmic reticulum (ER) as well as a cluster of genes linked with Alzheimer’s disease. We suggest that the assembly of the Blimp1-UPR-ER transcription hub permits the coordinate activation of a wide spectrum of genes that collectively establish plasma cell identity.
2019-04-10 | GSE113014 | GEO
Project description:Recent studies have highlighted super-enhancers (SEs) as important regulatory elements for gene expression, but their intrinsic properties remain incompletely characterized. Through an integrative analysis of Hi-C and ChIP-seq data, we find that a significant fraction of SEs are hierarchically organized, containing both hub and non-hub enhancers. Hub enhancers share similar histone marks with non-hub enhancers, but are distinctly associated with cohesin and CTCF binding sites and disease-associated genetic variants. Genetic ablation of hub enhancers results in profound defects in gene activation and local chromatin landscape. As such, hub enhancers are the major constituents responsible for SE functional and structural organization.
2018-01-27 | GSE107726 | GEO
Project description:Mycoplasma hyorhinis HUB-1 genome project
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Project description:ERN1/IRE1alpha is an endoplasmic reticulum sensor that recognizes misfolded proteins to activate the unfolded protein response. We used cholera toxin (CTx), which activates IRE1alpha in cells, to understand how this occurs. In vitro, the A1 subunit of CTx (CTxA1) bound the IRE1alpha lumenal domain (IRE1alphaLD). Global unfolding was not required. Instead, IRE1alphaLD recognized a 7-residue motif within a metastable region of CTxA1 that was also found in other microbial and host proteins involved in IRE1alpha activation. Binding mapped to a pocket on IRE1alphaLD normally occupied by a segment of the C-terminal flexible loop implicated in IRE1alpha regulation. Mutation of the recognition motif blocked CTx-induced IRE1alpha activation in live cells. These findings describe a mechanism for substrate recognition by IRE1alpha that induces the unfolded protein response.
2023-04-19 | MSV000091745 | MassIVE
Project description:MicroRNA-382 silencing induces a mitonuclear protein imbalance and activates the mitochondrial unfolded protein response in muscle cells
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Project description:VEGF is a major driver of blood vessel formation. However, the signal transduction pathways culminating into the biological consequences of VEGF signaling are partially understood. Here we show that the Hippo pathway effectors YAP and TAZ, work as a regulatory hub in mediating VEGF-VEGFR2 signaling during angiogenesis. We demonstrate that YAP/TAZ are essential for vascular development as endothelium specific deletion of YAP/TAZ leads to impaired vascularization and embryonic lethality. Mechanistically, we show that VEGF activates YAP/TAZ via its effects on actin cytoskeleton remodeling, and that activated YAP/TAZ induce a transcriptional program that results in the expression of a set of genes to further control cytoskeleton dynamics, and thus ensure a proper angiogenic response. YAP/TAZ deletion also results in VEGFR2 trafficking defects from the Golgi to the plasma membrane. Together, our study establishes YAP/TAZ as a central regulatory hub that mediates VEGF signaling, and hence, regulates angiogenesis.
2019-03-12 | GSE94856 | GEO
Project description:VEGF is a major driver of blood vessel formation. However, the signal transduction pathways culminating into the biological consequences of VEGF signaling are partially understood. Here we show that the Hippo pathway effectors YAP and TAZ, work as a regulatory hub in mediating VEGF-VEGFR2 signaling during angiogenesis. We demonstrate that YAP/TAZ are essential for vascular development as endothelium specific deletion of YAP/TAZ leads to impaired vascularization and embryonic lethality. Mechanistically, we show that VEGF activates YAP/TAZ via its effects on actin cytoskeleton remodeling, and that activated YAP/TAZ induce a transcriptional program that results in the expression of a set of genes to further control cytoskeleton dynamics, and thus ensure a proper angiogenic response. YAP/TAZ deletion also results in VEGFR2 trafficking defects from the Golgi to the plasma membrane. Together, our study establishes YAP/TAZ as a central regulatory hub that mediates VEGF signaling, and hence, regulates angiogenesis.
2019-03-12 | GSE94860 | GEO
Project description:Inadequate extracellular conditions can adversely affect the environment of the ER and impinge on the maturation of nascent proteins. The resultant accumulation of unfolded proteins activates a signal transduction pathway, known as the unfolded protein response, which serves primarily to protect the cell during stress and helps restore homeostasis to the ER. Microarray analysis of the unfolded protein response in a human medulloblastoma cell line treated with thapsigargin revealed that, in addition to known targets, a large number of proangiogenic factors were up-regulated. Real-time PCR analyses confirmed that four of these factors, VEGF, FGF2, angiogenin and IL-8, were transcriptionally up-regulated in multiple cell lines by various ER stress inducers. Our studies on VEGF regulation revealed that XBP-1(S), a UPR-inducible transcription factor, bound to two regions on the VEGF promoter, and analysis of XBP-1 null mouse embryonic fibroblasts revealed that it contributes to VEGF expression in response to ER stress. ATF4, another UPR-inducible transcription factor, also binds to the VEGF gene, although its contribution to VEGF transcription appeared to be fairly modest. We also found that VEGF mRNA stability is increased in response to UPR activation, via activation of the AMP and p38MAP kinases, demonstrating that increased mRNA levels occur at two regulatory points. In keeping with the mRNA levels, we found that VEGF protein is secreted at levels as high as or higher than that achieved in response to hypoxia. Our results indicate that the UPR plays a significant role in inducing positive regulators of angiogenesis. It also regulates VEGF expression at multiple levels and is likely to have widespread implications for promoting angiogenesis in response to normal physiological cues as well as in pathological conditions like cancer. We used microarrays to perform genome wide expression analysis in Daoy medulloblastoma cells to identify gene profiles that change in response to thapsigargin treatment which causes induction of the unfolded protein response.
2011-05-13 | E-GEOD-21979 | biostudies-arrayexpress
Project description:Nuclear and mitochondrial organelles must maintain a communication system. Loci on the mitochondrial genome were recently reported to interact with nuclear loci. To determine whether this is part of a DNA based communication system we used genome conformation capture to map the global network of DNA-DNA interactions between the mitochondrial and nuclear genomes (Mito-nDNA) in Saccharomyces cerevisiae cells grown under three different metabolic conditions. The interactions that form between mitochondrial and nuclear loci are dependent on the metabolic state of the yeast. Moreover, the frequency of specific mitochondrial - nuclear interactions (i.e. COX1-MSY1 and Q0182-RSM7) showed significant reductions in the absence of mitochondrial encoded reverse transcriptase machinery. Furthermore, these reductions correlated with increases in the transcript levels of the nuclear loci (MSY1 and RSM7). We propose that these interactions represent an inter-organelle DNA mediated communication system and that reverse transcription of mitochondrial RNA plays a role in this process. Genome Conformation Capture (GCC) has been performed on exponentially growing Saccharomyces cerevisiae cultures in glucose containing media. Paired end sequencing on an Illumina Genome Analyser was performed before the sequences were analysed by the propieatry software Topography 1.19. Inter- and intra- chromosomal interactions were mapped onto the S. cerevisiae S288 genome scaffold.
2013-01-17 | E-GEOD-33073 | biostudies-arrayexpress
Project description:The eukaryotic nucleus not only encloses meters of DNA, but also requires DNA to be differentially packaged in a cell-specific manner. Advances in chromosome-capture techniques have made great progress in understanding intra-chromosomal interactions. Yet, the mechanistic identities of homologous or non-homologous inter-chromosomal contacts (HCCs or NHCCs) remain elusive. Recently, two long non-coding RNA loci, CISTR-ACT and FIRRE, have been observed at NHCCs and implicated in human disease. Based on single nucleotide polymorphisms (SNPs), we developed an allele-specific CRISPR live-cell DNA imaging technique, named SNP-CLING, to describe primary locus characteristics across space and time. We observed allele-specific gene positioning, frequencies of HCCs or NHCCs, their motility and stability, and their positioning at the distinct sub-nuclear compartment of the nucleolus. Collectively, we define allele-specific locus properties and dynamics, and uncover an important new layer of genome organization in live cells.
2019-01-31 | GSE99657 | GEO