The RNA-binding proteins Roquin-1 and Regnase-1 interact and cooperate to prevent autoimmunity
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ABSTRACT:
PROVIDER: PRJNA641085 | ENA |
REPOSITORIES: ENA
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Project description:This study aimed to analyze the transcriptomic changes occuring after knockout of alleles encoding for the RNA-binding proteins Roquin-1 and Roquin-2 (DKO), Regnase-1 (KO) or a combination of all three (TKO) in Th1 cells without or after restimulation with anti-CD3/28 antibodies. Data analysis revealed that in unstimulated as well as restimulated T cells of all three knockout genotypes a number of genes is differentially expressed compared to WT cells, with the strongest deregulation seen in TKO cells. A comparison of gene expression changes of all three genotypes indicated that cooperativity of Roquin and Regnase-1 is the prevalent mode of target regulation.
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Project description:To investigate the effect of Regnase-1 and/or Roquin-1 disruption in engineered primary human T cells, we produced CAR-T cells and TCR-T cells with single genetic disruption of Regnase-1, Roquin-1, or dual disruption of Regnase-1 and Roquin-1. We then performed differential gene expression analysis using data obtained from bulk RNA-seq of 3 different biological donors at baseline.
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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: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.
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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.
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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.
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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.
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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.
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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.
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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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