Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA277061 | ENA |
REPOSITORIES: ENA
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Project description:MicroRNAs (miRNAs) regulate gene expression and generate isoforms (isomiRs) with distinct targeting properties, but their roles in cellular specification and reprogramming remain poorly understood. Here, we investigated miRNAs and isomiRs during direct reprogramming to conventional type 1 dendritic cells (cDC1s), identifying miR-124 and miR-142 as facilitators of the process. The canonical miR-124-3p strand induced a permissive chromatin landscape enriched for cooperative transcription factor motifs, thereby transiently increasing reprogramming efficiency. In contrast, miR-142 enhanced lineage fidelity by repressing fibroblast identity and activating cDC1-specific programs through cooperating isomiRs that drove XCR1 expression and increased type III interferon production. In addition, miR-142 mimics enhanced cancer cell reprogramming and anti-tumor immunity in vivo. Finally, we developed RNA-based cDC1 reprogramming using transcription factor mRNAs combined with miRNA mimics. Together, these findings uncover miRNA isoform diversity as a programmable regulatory layer in immune cell specification and establish RNA-driven reprogramming as a non-viral strategy for cancer immunotherapy.
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Project description:MicroRNAs (miRNAs) regulate gene expression and generate isoforms (isomiRs) with distinct targeting properties, but their roles in cellular specification and reprogramming remain poorly understood. Here, we investigated miRNAs and isomiRs during direct reprogramming to conventional type 1 dendritic cells (cDC1s), identifying miR-124 and miR-142 as facilitators of the process. The canonical miR-124-3p strand induced a permissive chromatin landscape enriched for cooperative transcription factor motifs, thereby transiently increasing reprogramming efficiency. In contrast, miR-142 enhanced lineage fidelity by repressing fibroblast identity and activating cDC1-specific programs through cooperating isomiRs that drove XCR1 expression and increased type III interferon production. In addition, miR-142 mimics enhanced cancer cell reprogramming and anti-tumor immunity in vivo. Finally, we developed RNA-based cDC1 reprogramming using transcription factor mRNAs combined with miRNA mimics. Together, these findings uncover miRNA isoform diversity as a programmable regulatory layer in immune cell specification and establish RNA-driven reprogramming as a non-viral strategy for cancer immunotherapy.
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Project description:MicroRNAs (miRNAs) regulate gene expression and generate isoforms (isomiRs) with distinct targeting properties, but their roles in cellular specification and reprogramming remain poorly understood. Here, we investigated miRNAs and isomiRs during direct reprogramming to conventional type 1 dendritic cells (cDC1s), identifying miR-124 and miR-142 as facilitators of the process. The canonical miR-124-3p strand induced a permissive chromatin landscape enriched for cooperative transcription factor motifs, thereby transiently increasing reprogramming efficiency. In contrast, miR-142 enhanced lineage fidelity by repressing fibroblast identity and activating cDC1-specific programs through cooperating isomiRs that drove XCR1 expression and increased type III interferon production. In addition, miR-142 mimics enhanced cancer cell reprogramming and anti-tumor immunity in vivo. Finally, we developed RNA-based cDC1 reprogramming using transcription factor mRNAs combined with miRNA mimics. Together, these findings uncover miRNA isoform diversity as a programmable regulatory layer in immune cell specification and establish RNA-driven reprogramming as a non-viral strategy for cancer immunotherapy.
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Project description:MicroRNAs (miRNAs) regulate gene expression and generate isoforms (isomiRs) with distinct targeting properties, but their roles in cellular specification and reprogramming remain poorly understood. Here, we investigated miRNAs and isomiRs during direct reprogramming to conventional type 1 dendritic cells (cDC1s), identifying miR-124 and miR-142 as facilitators of the process. The canonical miR-124-3p strand induced a permissive chromatin landscape enriched for cooperative transcription factor motifs, thereby transiently increasing reprogramming efficiency. In contrast, miR-142 enhanced lineage fidelity by repressing fibroblast identity and activating cDC1-specific programs through cooperating isomiRs that drove XCR1 expression and increased type III interferon production. In addition, miR-142 mimics enhanced cancer cell reprogramming and anti-tumor immunity in vivo. Finally, we developed RNA-based cDC1 reprogramming using transcription factor mRNAs combined with miRNA mimics. Together, these findings uncover miRNA isoform diversity as a programmable regulatory layer in immune cell specification and establish RNA-driven reprogramming as a non-viral strategy for cancer immunotherapy.
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Project description:MicroRNAs (miRNAs) regulate gene expression and generate isoforms (isomiRs) with distinct targeting properties, but their roles in cellular specification and reprogramming remain poorly understood. Here, we investigated miRNAs and isomiRs during direct reprogramming to conventional type 1 dendritic cells (cDC1s), identifying miR-124 and miR-142 as facilitators of the process. The canonical miR-124-3p strand induced a permissive chromatin landscape enriched for cooperative transcription factor motifs, thereby transiently increasing reprogramming efficiency. In contrast, miR-142 enhanced lineage fidelity by repressing fibroblast identity and activating cDC1-specific programs through cooperating isomiRs that drove XCR1 expression and increased type III interferon production. In addition, miR-142 mimics enhanced cancer cell reprogramming and anti-tumor immunity in vivo. Finally, we developed RNA-based cDC1 reprogramming using transcription factor mRNAs combined with miRNA mimics. Together, these findings uncover miRNA isoform diversity as a programmable regulatory layer in immune cell specification and establish RNA-driven reprogramming as a non-viral strategy for cancer immunotherapy.
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Project description:MicroRNAs (miRNAs) post-transcriptionally regulate gene expression by inhibiting protein synthesis of target messenger RNAs (mRNAs). MicroRNA-142 (miR-142), which has tumor-suppressive properties, was functionally deleted by CRISPR/Cas9 knockout in cell lines derived from diffuse large B-cell lymphoma (DLBCL), a highly aggressive tumor that represents about 30% of non-Hodgkin lymphoma worldwide. Mutations in miR-142 affect about 20% of all cases of DLBCL. By proteome analyses, the miR-142 knockout resulted in a consistent up-regulation of 52 but also down-regulation of 41 proteins in the GC-DLBCL lines BJAB and SUDHL4. Various mitochondrial ribosomal proteins were up-regulated in line with their pro-tumorigenic properties, while proteins necessary for MHC-I presentation were down-regulated in accordance with the finding that miR-142 knockout mice have a defective immune response. Of the deregulated proteins/genes, CFL2, CLIC4, STAU1, and TWF1 are known targets of miR-142, and we could additionally confirm AKT1S1, CCNB1, LIMA1, and TFRC as new targets of miR-142-3p or -5p. We further show that seed-sequence mutations of miR-142 can be used to confirm potential targets and that miRNA knockout cell lines might thus be used to identify novel targets of miRNAs. Due to the complex contribution of miRNAs within cellular regulatory networks, in particular when a miRNA highly present in the RISC complex is deleted and can be replaced by other endogenous miRNAs, primary effects on gene expression may be covered by secondary layers of regulation
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Project description:MicroRNAs (miRNAs, micro ribonucleic acids) are pivotal post-transcriptional regulators of gene expression. These endogenous small non-coding RNAs play significant roles in tumorigenesis and tumor progression. miR-142-3p expression is dysregulated in several breast cancer subtypes. We aimed at investigating the role of miR-142-3p in breast cancer cell invasiveness. Supported by transcriptomic Affymetrix array analysis and confirmatory investigations at the mRNA and protein level, we demonstrate that overexpression of miR-142-3p in MDA-MB-231, MDA-MB-468 and MCF-7 breast cancer cells leads to downregulation of WASL (Wiskott-Aldrichsyndrome-like, protein: N-WASP), Integrin-aV, RAC1, and CFL2, molecules implicated in cytoskeletal regulation and cell motility. ROCK2, IL6ST, KLF4, PGRMC2 and ADCY9 were identified as additional targets in a subset of cell lines. Decreased matrigel invasiveness was associated with the miR-142-3p-induced expression changes. Confocal immunofluorescence microscopy, nanoscale atomic force microscopy and digital holographic microscopy revealed a change in cell morphology as well as a reduced cell volume and size. A more cortical actin distribution and a loss of membrane protrusions were observed in cells overexpressing miR-142-3p. Luciferase activation assays confirmed direct miR-142-3p-dependent regulation of the 3'-untranslated region of ITGAV and WASL. siRNA-mediated depletion of ITGAV andWASL resulted in a significant reduction of cellular invasiveness, highlighting the contribution of these factors to the miRNA-dependent invasion phenotype. While knockdown of WASL significantly reduced the number of membrane protrusions compared to controls, knockdown of ITGAV resulted in a decreased cell volume, indicating differential contributions of these factors to the miR-142-3p-induced phenotype. Our data identify WASL, ITGAV and several additional cytoskeleton associated molecules as novel invasion-promoting targets of miR-142-3p in breast cancer.
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