Transcriptome analysis of LPS-stimulated BMDMs pretreated with Ctrl MO or Regnase-1-targeting MOs (Reg1-MOs)
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PROVIDER: PRJNA757257 | ENA |
REPOSITORIES: ENA
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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’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.
2022-03-28 | GSE182641 | GEO
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
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.
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Project description:Transcriptiome profiling of SMN MO injected, Gemin2 MO injected zebrafish embryos vs Control MO injected
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Project description:miRNA profiling of zebrafish embryos comparing control MO with Lin28A MO or Lin28B MO injected embryos at 5hpf
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Project description:Post-transcriptional regulation of immune-related transcripts by RNA-binding proteins (RBPs) impacts immune cell responses, including mast cell functionality. Despite their importance in immune regulation, the functional role of most RBPs remains to be understood. By manipulating the expression of specific RBPs in murine mast cells, coupled with mass spectrometry and transcriptomic analyses, we found that the Regnase family of proteins acts as a potent regulator of mast cell physiology. Specifically, Regnase-1 is required to maintain basic cell proliferation and survival, while both Regnase-1 and -3 cooperatively regulate the expression of inflammatory transcripts upon activation, with Tnf being a primary target in both human and mouse cells. Further, Regnase-3 directly interacts with Regnase-1 in mast cells and is necessary to restrain Regnase-1 expression through the destabilization of its transcript. Overall, our study identifies protein interactors of endogenously expressed Regnase factors, characterizes the regulatory interplay between Regnase family members in mast cells, and establishes their role in the control of mast cell homeostasis and inflammatory responses.
2024-05-31 | PXD051849 | Pride
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
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
Project description:Dysregulation of mast cell activation can lead to allergic and anaphylactic reactions. Post-transcriptional regulation of immune-related transcripts by RNA-binding proteins (RBPs) is critical in controlling immune cell responses, including mast cell functionality. The Regnase family of RBPs plays a central role in regulating gene expression and controlling immune responses in both lymphoid and myeloid cells. However, what is the functional role of Regnase proteins in mast cells remains to be understood. Using different approaches of Regnase proteins depletion and deletion as well as overexpression by mRNA delivery, we found that Regnase-1 is a powerful negative regulator of mast cell proliferation, survival and ability to produce inflammatory cytokines. On the other hand, Regnase-3 was essential to modulate Regnase-1 expression in mast cells by direct targeting of the 3’-untranslated region of Regnase-1, leading to the destabilization of the Zc3h12a mRNA. Regnase-1 deletion had widespread effect on mast proliferation and survival even in the absence of stimulation and was at least in part linked to specific nuclear functions of Regnase-1 in modulating the ability of mast cells to withstand DNA damage. Overall, we describe the importance of Regnase proteins in modulating mast cell homeostatic and inflammatory responses and we describe the impact of Regnase-1 in the maintenance of genome stability.
2024-05-31 | GSE240035 | GEO
Project description:Dysregulation of mast cell activation can lead to allergic and anaphylactic reactions. Post-transcriptional regulation of immune-related transcripts by RNA-binding proteins (RBPs) is critical in controlling immune cell responses, including mast cell functionality. The Regnase family of RBPs plays a central role in regulating gene expression and controlling immune responses in both lymphoid and myeloid cells. However, what is the functional role of Regnase proteins in mast cells remains to be understood. Using different approaches of Regnase proteins depletion and deletion as well as overexpression by mRNA delivery, we found that Regnase-1 is a powerful negative regulator of mast cell proliferation, survival and ability to produce inflammatory cytokines. On the other hand, Regnase-3 was essential to modulate Regnase-1 expression in mast cells by direct targeting of the 3’-untranslated region of Regnase-1, leading to the destabilization of the Zc3h12a mRNA. Regnase-1 deletion had widespread effect on mast proliferation and survival even in the absence of stimulation and was at least in part linked to specific nuclear functions of Regnase-1 in modulating the ability of mast cells to withstand DNA damage. Overall, we describe the importance of Regnase proteins in modulating mast cell homeostatic and inflammatory responses and we describe the impact of Regnase-1 in the maintenance of genome stability.
2024-05-31 | GSE240095 | GEO