Ca2+ influx through ORAI1 and ORAI2 channels regulates chromatin accessibility in CD4+ T cells
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ABSTRACT:
PROVIDER: PRJNA1064170 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27532300_1.fastq.gz | Fastqsanger.gz | |||
| SRR27532300_2.fastq.gz | Fastqsanger.gz | |||
| SRR27532301_1.fastq.gz | Fastqsanger.gz | |||
| SRR27532301_2.fastq.gz | Fastqsanger.gz | |||
| SRR27532302_1.fastq.gz | Fastqsanger.gz |
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Project description:Activation of CD4+ T cells by T cell receptor (TCR) signaling results in altered gene expression as a result of epigenetic and transcriptional regulation. A critical TCR signaling pathway in CD4+ T cells is driven by Ca2+ influx across the plasma membrane through Ca2+ release-activated Ca2+ (CRAC) channels that are formed by ORAI1 and ORAI2 proteins. Here we analyzed the effects of suppressing Ca2+ influx in mouse CD4+ T cells on chromatin accessibility by genetically deleting the ORAI1 channel alone or both ORAI1 and ORAI2 channels. CD4+ T cells specific for ovalbumin (OVA) from TCR transgenic OT-II were activated by in vivo exposure to influenza A virus (IAV) expressing OVA neoantigen. Changes in chromatin accessibility of CD4+ T cells in response to IAV-OVA infection were determined by ATAC sequencing
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Project description:Calcium signals are initiated in immune cells by the process of store-operated calcium entry (SOCE), where receptor activation triggers transient calcium release from the endoplasmic reticulum, followed by opening of plasma membrane calcium-release activated calcium (CRAC) channels. ORAI1, ORAI2 and ORAI3 are known to comprise the CRAC channel, however the contributions of individual isoforms to neutrophil function is not well understood. Here we show that loss of ORAI1 partially decreases calcium influx while loss of both ORAI1 and ORAI2 completely abolishes store-operated calcium entry. In other immune cell types, loss of ORAI2 enhances SOCE. In contrast, we find that ORAI2-deficient neutrophils display decreased calcium influx, which is correlated with measurable differences in regulation of neutrophil membrane potential via KCa3.1. Decreased SOCE in ORAI1-, ORAI2- and ORAI1/2-deficient neutrophils impairs multiple neutrophil functions including phagocytosis, degranulation, leukotriene and ROS production, rendering ORAI1/2-deficient mice highly susceptible to staphylococcal infection. This study demonstrates that ORAI1 and ORAI2 are the primary components of the neutrophil CRAC channel and identifies novel subpopulations of neutrophils where cell membrane potential functions as a rheostat to modulate the SOCE response. These findings have implications for new mechanisms that modulate neutrophil function during infection, acute and chronic inflammatory conditions, and cancer.
2020-09-01 | GSE157200 | GEO
Project description:Oral cancer causes pain associated with cancer progression. The mechanism(s) underlying the pain is not fully understood. We report here that the function of the Ca2+ channel ORAI1 is an important regulator of oral cancer pain. ORAI1 was highly expressed in tumor samples from oral cancer patients and ORAI1 activation caused sustained Ca2+ influx in human oral cancer cells. RNA-seq analysis showed broad modulation of oral cancer markers such MMPs and pain modulators by ORAI1. Inoculation of oral cancer cells lacking ORAI1 into mouse paws reduced ectopic tumor growth and allodynia, reducing secreted MMP1 levels and the excitation of trigeminal ganglia (TG) neurons. The stimulation of TG neurons with MMP1 evoked an increase in action potentials. These data demonstrate an important role of ORAI1 in oral cancer progression likely by controlling the expression of MMP1 resulting in increased cancer progression and pain
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Project description:Tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) are clinically overlapping disorders characterized by childhood-onset muscle weakness and a variable occurrence of multi-systemic signs including short stature, thrombocytopenia, and hyposplenism. TAM/STRMK is caused by gain-of-function mutations in the Ca2+ sensor STIM1 or the Ca2+ channel ORAI1, both regulating Ca2+ homeostasis through the ubiquitous SOCE (store-operated Ca2+ entry) mechanism. Functional experiments in cells have demonstrated that the TAM/STRMK mutations induce SOCE overactivation, resulting in excessive influx of extracellular Ca2+. There is currently no treatment for TAM/STRMK, but SOCE is amenable to manipulation. Here we crossed Stim1R304W/+ mice harboring the most common TAM/STRMK mutation with Orai1R93W/+ mice carrying an ORAI1 mutation partially obstructing Ca2+ influx. Compared with Stim1R304W/+ littermates, Stim1R304W/+Orai1R93W/+ offspring showed a normalization of bone architecture, spleen histology, and muscle morphology, an increase of thrombocytes, and improved muscle contraction and relaxation kinetics. Accordingly, comparative RNA- sequencing detected more than 1200 dysregulated genes in Stim1R304W/+ mice and revealed a major restoration of gene expression in Stim1R304W/+Orai1R93W/+ mice. Altogether, we provide physiological, morphological, functional, and molecular data highlighting the therapeutic potential of ORAI1 inhibition to rescue the multi-systemic TAM/STRMK signs, and we identified myostatin as a suitable biomarker for TAM/STRMK in human and mouse.
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Project description:X-ray causes mRNA transcripts change to enhance Orai2-meadated Ca2+ influx in rat brain microvascular endothelial cells
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Project description:Cell surface calcium (Ca2+) channels permit Ca2+ ion influx, with Ca2+ taking part in cellular functions such as proliferation, survival, and activation. The expression of voltage-dependent Ca2+ (CaV) channels may modulate the growth of hematologic cancers. Profile analysis of Ca2+ channels, with a focus on the L-type CaV channels, was performed on RNA sequencing data from lymphoma and leukemia cell lines and samples derived from patients with diffuse large B cell lymphoma (DLBCL). CaV1.2 expression was found to be elevated in classical Hodgkin lymphoma (CHL) cell lines when compared to other B cell lymphoma cell lines. In our analysis comparing activated B cell-like DLBCL (ABC-DLBCL) and germinal centre B cell-like DLBCL (GCB-DLBCL) patient samples, ABC-DLBCL revealed stronger expression of CaV1.3, whereas CaV1.1, CaV1.2, and CaV1.4 showed greater expression levels in GCB-DLBCL. As Ca2+ is known to bind to calmodulin, leading to calcineurin activation and the passage of nuclear factor of activated T cells (NFAT) to the cell nucleus, pathways for calcineurin, calmodulin, NFAT, and Ca2+ signaling were also analyzed by gene set enrichment analysis. The NFAT and Ca2+ signaling pathways were found to be upregulated in the CHL cell lines relative to other B cell lymphoma cell lines. Furthermore, the calmodulin and Ca2+ signaling pathways were shown to be downregulated in the ABC-DLBCL patient samples. The findings of this study suggest that L-type CaV channels and Ca2+-related pathways could serve as differentiating components for biologic therapies to target hematological cancers.
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Project description:We showed that the overexpression of ORAI1 in the neurons of murine brain leads to spontaneous occurrence of seizure-like events in aged animals. We aimed to identify the mechanism responsible for this phenomenon. Using modified Ca2+-addback assay in the slices of CA1 hippocampal region and FURA-2AM calcium indicator we found that overexpression of ORAI1 in neurons leads to altered Ca2+ response. Next, by RNASeq we identified set of genes, whose expression was changed in FVB/NJ-Tg(ORAI1)Ibd mice.
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Project description:T cell activation following antigen binding to the T cell receptor (TCR) involves the mobilization of intracellular calcium (Ca2+) to activate the key transcription factors NFAT and NF-κB. The mechanism of NFAT activation by Ca2+ has been determined; however, the role of Ca2+ in controlling NF-κB signaling is poorly understood and the source of Ca2+ required for NF-κB activation is unknown. We demonstrate that TCR- but not TNF- induced NF-κB signaling upstream of IκB kinase (IKK) activation absolutely requires the influx of extracellular Ca2+ via STIM1-dependent CRAC/Orai channels. We further show that Ca2+ influx controls phosphorylation of the NF-κB protein p65 on Ser536 and that this post- translational modification controls its nuclear localization and transcriptional activation. Notably our data reveal that this role for Ca2+ is entirely separate from its upstream control of IκBα degradation, thereby identifying a novel Ca2+- dependent distal step in TCR-induced NF-κB activation. Finally, we demonstrate that this control of distal signaling occurs via Ca2+-dependent PKCk-mediated phosphorylation of p65. Thus, we establish the source of Ca2+ required for TCR induced NF-kB activation and we define a new distal Ca2+-dependent checkpoint in TCR-induced NF-kB signaling that has broad implications for the control of immune cell development and T cell functional specificity. 3 treatments were analyzed, with biological replicates for each treatment. In addition, three timepoints (1 hour, 4 hour, and 8 hour) were examined for each treatment, as well as an untreated control. In total 19 samples were analyzed
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