Transcriptome analysis of LPS-stimulated BMDMs pretreated with Ctrl MO or Regnase-1-targeting MOs (Reg1-MOs)
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA757257 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15594000.fastq.gz | Fastqsanger.gz | |||
| SRR15594001.fastq.gz | Fastqsanger.gz | |||
| SRR15594002.fastq.gz | Fastqsanger.gz | |||
| SRR15593987.fastq.gz | Fastqsanger.gz | |||
| SRR15593988.fastq.gz | Fastqsanger.gz |
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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'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.
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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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