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Transcriptome analysis of LPS-stimulated BMDMs pretreated with Ctrl MO or Regnase-1-targeting MOs (Reg1-MOs)

ABSTRACT: Regnase-1 plays essential roles in restricting inflammation by acting as a RNase degrading mRNAs involved in immune reactions via the recognition of stem-loop structures in the 3’untranslated regions (UTRs). Dysregulated expression of Regnase-1 is implicated in the pathogenesis of inflammatory and autoimmune diseases in mice and humans. Here we developed a novel therapeutic strategy to suppress inflammatory responses by blocking Regnase-1 self-regulation, which was enabled by the simultaneous use of two antisense phosphorodiamidate morpholino oligonucleotides (MOs) to alter the binding affinity of Regnase-1 towards the stem-loop structures present in its 3’UTR. The Regnase-1-targeting MOs successfully stabilized Regnase-1 mRNA expression. Furthermore, increasing the abundance of Regnase-1 by MO treatment effectively reduced multiple pro-inflammatory transcripts that were controlled by Regnase-1 in BMDMs. Collectively, these data suggested that MO-mediated disruption of the Regnase-1 self-regulation pathway is an attractive therapeutic strategy to enhance Regnase-1 abundance, which could provide clinical benefits for treating inflammatory diseases through the suppression of inflammation.

ORGANISM(S): Mus musculus

PROVIDER: GSE182641 | GEO | 2022/03/28

REPOSITORIES: GEO

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Single-cell transcriptional changes of spinal cord immune cells associated with Reg1-MO treatment during EAE neuroinflammation

Project description:Regnase-1 plays essential roles in restricting inflammation by acting as a RNase degrading mRNAs involved in immune reactions via the recognition of stem-loop structures in the 3'UTRs. Here we developed a novel therapeutic strategy to suppress inflammatory responses by upregulating Regnase-1 expression, which was enabled by the simultaneous use of two antisense morpholino oligonucleotides (MOs) to alter the stem-loop structures present in the Regnase-1 3'UTR and inhibit its auto-regulation. Intracranial Reg1-MO treatment successfully altenuated the disease severity of EAE, with significant delay in disease onset and lower incidence of paralysis. To clarify the cell types responsible for the suppression of autoimmune responses by Reg1-MOs in the CNS, we performed single-cell RNA sequencing (scRNA-seq) using the 10X Chromium platform using the spinal cord CD45+ cells derived from control and Reg1-MO groups collected at the peak of disease (D16). We found that Reg1-MO treatment not only stalled the microglial activation, but also increased the suppressive fucntion of regulatory T cells.

2022-03-28 | GSE182646 | GEO

Transcriptome analysis of LPS-stimulated BMDMs pretreated with Ctrl MO or Regnase-1-targeting MOs (Reg1-MOs)

Project description:Transcriptome analysis of LPS-stimulated BMDMs pretreated with Ctrl MO or Regnase-1-targeting MOs (Reg1-MOs)

| PRJNA757257 | ENA

Effect of loss of Regnase-1 and Regnase-3 on the transcriptional profile in mouse Lin–Sca1+Kit+ (LSK) cells

Project description:Regulation of lineage biases in hematopoietic stem and progenitor cells (HSPCs) is pivotal for balanced hematopoietic output. However, little is known about the mechanism behind lineage choice in HSPCs. Here, we show that mRNA decay factors Regnase-1 (Zc3h12a) and Regnase-3 (Zc3h12c) are critical for induction of myeloid lineage priming, restricting lymphoid differentiation in HSPCs. Regnase-1- and Regnase-3-mediated control of mRNA encoding Nfkbiz, a transcriptional and epigenetic regulator, was essential for balancing lymphoid/myeloid lineage output in HSPCs in vivo. Furthermore, single cell-assay for transposase-accessible chromatin sequencing (scATAC-seq) analysis revealed that Regnase-1 and Regnase-3 control the epigenetic landscape on myeloid-related gene loci in hematopoietic stem cells (HSCs) via Nfkbiz. Consistently, an antisense oligonucleotide designed to inhibit Regnase-1- and Regnase-3-mediated Nfkbiz mRNA degradation primed HSCs toward myeloid lineages by enhancing Nfkbiz expression. Collectively, the collaboration between post-transcriptional control and chromatin remodeling by the Regnase-1/Regnase-3-Nfkbiz axis governs lineage priming, instructing HSC lineage specification.

2024-02-09 | GSE228923 | GEO

Immune homeostasis and regulation of the Interferon pathway require myeloid-derived Regnase-3

Project description:The RNase Regnase-1 is a master RNA regulator in macrophages and T cells that degrades cellular and viral RNA upon NF-kB signaling. The roles of the other Regnase family-members remain largely unknown. Here, we analyze Regnase-3 deficient mice, which develop hypertrophic lymph nodes. We used various mice with immune cell specific deletions of Regnase-3 to demonstrate that Regnase-3 acts specifically within myeloid cells. Regnase-3 deficiency systemically increased interferon signaling, which increased the proportion of immature B and innate immune cells and suppressed follicles and germinal center formation. Expression analysis revealed that Regnase-3 and Regnase-1 share protein degradation pathways. Nevertheless, Regnase-3 expression is specifically high in macrophages and transcriptionally controlled by interferon signaling. Although direct targets in macrophages remain unknown, Regnase-3 can bind, degrade and regulate mRNAs, such Zc3h12a encoding Regnase-1, in vitro. These data indicate that Regnase-3, like Regnase-1, is an RNase and essential for immune homeostasis, but has diverged as a key regulator for the interferon pathway in macrophages.

2019-04-05 | GSE129325 | GEO

Regnase-1 overexpression/knockdown effect on primary mouse articular chondrocytes

Project description:Gene expression profiling of primary mouse articular chondrocyte infected with recombinant adenovirus expression mouse Regnase-1 or recombinant adenovirus expressing mouse small hairpin RNA of Regnase-1. In this study, we have attempted to explore the effects of Regnase-1 overexpression or knockdown on mouse transcriptome and have identified numerous genes which are involved in osteoarthritis pathogenesis.

2021-01-01 | GSE153179 | GEO

Patient-derived micro-organospheres (MOS) enable clinical precision oncology

Project description:Patient-derived xenografts (PDX) and organoids (PDO) have been shown to model clinical response to cancer therapy. However, it remains challenging to use these models to guide timely clinical decisions for cancer patients. Here we used droplet emulsion microfluidics with temperature control and dead-volume minimization to rapidly generate thousands of Micro- Organospheres (MOS) from low-volume patient tissues, which serve as an ideal patient-derived model for clinical precision oncology. A clinical study of newly diagnosed metastatic colorectal cancer (CRC) patients using a MOS-based precision oncology pipeline reliably predicted patient treatment outcome within 14 days, a timeline suitable for guiding treatment decisions in clinic. Furthermore, MOS capture original stromal cells and allow T cell penetration, providing a clinical assay for testing immuno-oncology (IO) therapies such as PD-1 blockade, bispecific antibodies, and T cell therapies on patient tumors.

2022-09-01 | GSE184242 | GEO

Effect of Regnase-2/MCPIP2/ZC3H12B overexpression in human glioblastoma U-251 MG cell line.

Project description:Regnase-2/MCPIP2/ZC3H12B is a protein belonging to the ZC3H12 protein family. There are three other proteins of this family present in humans of which Regnase-1/MCPIP1/ZC3H12A is the founder member as well as the best-described protein. All proteins of this family contain a NYN domain with endoribonuclease activity and a CCCH-type zinc finger responsible for interaction with substrate RNA. Although the NYN domain has a high degree of similarity across all four members the in vitro RNase activity was shown only for two of them, namely Regnase-1 and Regnase-3. Interestingly the ZC3H12 family proteins have unique expression patterns with Regnase-2 being expressed almost solely in the central nervous system. What is more, Regnase-2 is downregulated in human glioblastoma, and its expression is inversely correlated with tumor grade. To decipher the role of Regnase-2 in human glioblastoma we performed RNA sequencing of U-251 MG cells overexpressing Regnase-2 and control, mock-transfected cells.

2024-01-24 | GSE248634 | GEO

Transcriptome analysis of Regnase-1 deficient B cells at steady-state or upon B cell receptor stimulation

Project description:This study aims to identify the transcriptional programs that are regulated by the RNA binding protein Regnase-1 in B cells. To address the B cell specific roles of Regnase-1, we performed RNA seq analysis of B cells isolated from the spleens of mice in which Regnase-1 was deleted in a B cell specific manner using an inducible cre recombinase model, referred to as Regnase-1f/f hCD20TamCre, and compared to the appropriate controls, referred to as Regnase-1+/+ hCD20TamCre. Determining the differentially expressed genes from Regnase-1 deficient B cells compared to the control cells enabled identification of the transcriptional program regulated by Regnase-1 in B cells during steady state. In addition, we analyzed Regnase-1 deficient and control B cells that were stimulated with a stimulatory anti-IgM F(ab’)2 antibody that engages the B cell receptor (BCR). BCR engagement results into activation of B cells. Therefore, the differentially expressed genes from this analysis enabled identification of the genes that are modulated by Regnase-1 in B cells during an activated state.

2021-03-01 | GSE147799 | GEO

Expression data comparing human DKK1 and control vector transfected murine osteochondrosarcoma cells (MOS-J)

Project description:Canonical Wnt signaling controls proliferation and differentiation of osteogenic progenitor cells, and tumor-derived secretion of the Wnt antagonist Dickkopf-1 (Dkk1) is correlated with osteolyses and metastasis in many bone malignancies. However, the role of Dkk1 in the oncogenesis of primary osteosarcoma (OS) remains unexplored. Here, we over-expressed Dkk1 in the OS cell line MOS-J. Contrary to expectations, Dkk1 had autocrine effects on MOSJ cells in that it increased proliferation and resistance to metabolic stress in vitro. In vivo, Dkk1 expressing MOS-J cells formed larger and more destructive tumors than controls. These effects were attributed in part to up-regulation of the stress response enzyme and cancer stem cell marker aldehyde-dehydrogenase-1 (ALDH1) through Jun-N-terminal kinase signaling. This is the first report linking Dkk1 to tumor stress resistance, further supporting the targeting of Dkk1 not only to prevent and treat osteolytic bone lesions but also to reduce numbers of stress-resistant tumor cells. Two samples were analyzed, one human DKK1 transfected MOS-J cell sample and one control vector transfected MOS-J cell sample.

2012-12-22 | E-GEOD-43112 | biostudies-arrayexpress

Improved persistence and expanded TPEX formation in Regnase-1 KO CAR T cells is TCF-1-dependent

Project description:transcriptional profiling was performed on Regnase-1 KO CAR and Regnase-1 TCF-1 DKO CAR T cells isolated 7days after co-transfer into tumor bearing mice. TCF-1 deficiency in Regnase-1 KO CAR T cells led to reduced long-term persistence and memory-like phenotype.

2021-04-07 | GSE155020 | GEO

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