MicroRNA-155 controls iNKT cell development and lineage differentiation by coordinating multiple regulating pathways
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ABSTRACT:
PROVIDER: PRJNA682399 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13192664.fastq.gz | Fastqsanger.gz | |||
| SRR13192665.fastq.gz | Fastqsanger.gz | |||
| SRR13192666.fastq.gz | Fastqsanger.gz | |||
| SRR13192667.fastq.gz | Fastqsanger.gz | |||
| SRR13192668.fastq.gz | Fastqsanger.gz |
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Project description:The development of invariant natural killer T (iNKT) cells requires a well-attuned set of transcription factors, but how these factors are regulated and coordinated remains poorly understood. MicroRNA-155 (miR-155) is a key regulator of numerous cellular processes that affects cell development and homeostasis. Here, we found that the miR-155 was highly expressed in early iNKT cells upon thymic section, and then its expression is gradually downregulated during iNKT cell development. However, the mice with miR-155 germline deletion had normal iNKT cell development. To address if downregulated miR-155 is required for iNKT cell development, we made a CD4Cre.miR-155 knock-in (KI) mouse model with miR-155 conditional overexpression in the T cell lineage. Upregulated miR-155 led to interruption of iNKT cell development, diminished iNKT17 and iNKT1 cells, augmented iNKT2 cells, and these defects were cell-intrinsic. Furthermore, defective iNKT cells in miR-155KI mice resulted in the secondary innate-like CD8 T cell development. Mechanistically, miR-155 modulated multiple targets and signaling pathways to fine tune iNKT cell development. MiR-155 modulated Jarid2, a critical component of a histone modification complex, and Tab2, the upstream activation kinase complex component of NF-kB, which function additively in iNKT development and in promoting balanced iNKT1/iNKT2 differentiation. In addition, miR-155 also targeted Rictor, a signature component of mTORC2 that controls iNKT17 differentiation. Taken together, our results indicate that miR-155 serves as a key epigenetic regulator, coordinating multiple signaling pathways and transcriptional programs to precisely regulate iNKT cell development and functional lineage, as well as secondary innate CD8 T cell development.
2021-12-21 | GSE162613 | GEO
Project description: Not available
| S-EPMC7874147 | biostudies-literature
Project description:CD1d expression by thymocytes is required to select iNKT cells. When CD1d is expressed only on thymocytes (pLck-CD1d tg mice), iNKT cells are hyperresponsive to antigen stimulation suggesting that, in physiological conditions, these cells undergo functional education mediated by additional CD1d-expressing cells. Here, we investigated the mechanisms of this functional education. We find that peripheral iNKT cells from pLck-CD1d tg mice express significantly less SHP-1, a tyrosine phosphatase negatively regulating TCR signaling, than WT cells. iNKT cells from heterozygous SHP-1-mutated motheaten mice, displaying similar SHP-1 reduction as pLck-CD1d tg iNKT cells, are antigen-hyperresponsive. Restoring normal CD1d expression in pLck-CD1d tg mice normalizes SHP-1 expression and responsiveness of iNKT cells. In WT mice, iNKT cells upregulate SHP-1 and decrease responsiveness upon emigration from thymus to periphery. This depends on contacts with CD1d-expressing DCs. iNKT cell functional education is therefore controlled by DCs via tuning SHP-1 expression level in the periphery. Hepatic iNKT cells from wild-type and transgenic mice (expressing hCD1d molecule under the pLck promoter)
2013-03-01 | E-GEOD-42835 | biostudies-arrayexpress
Project description:Deletion of Uhrf1 resulted in stage 1-specific defects during iNKT cell development. To investigate the molecular mechanism, we sorted WT and Uhrf1-KO stage 1 iNKT cells and performed RNA-seq. By comparing gene expression profile, we found metabolic defects in Uhrf1-KO stage 1 iNKT cells. The expression of CD71 (Tfrc), two subunits of CD98 (Slc3a2 and Slc7a5) and Glut3 (Slc2a3) was reduced in stage 1 iNKT cells. Besides, the downstream pathways of AKT-mTOR axis were significantly reduced. Collectively, our results suggest that Uhrf1 is required for iNKT cell development by regulating the Akt-mTOR signaling pathway. We first sorted WT and Uhrf1-KO stage 1 iNKT cells, extracted the mRNA and performed RNA-seq. We then analyzed the differentially expressed genes and performed KEGG pathway analysis. We used RT-PCR to verify the expression of the key nutrient related genes (Tfrc, Slc3a2, Slc7a5 and Slc2a3) and used flow cytometry to test the protein level of metabolic related molecules. Besides, we also analyzed the expression of genes of mTOR downstream pathways to demonstrate that Uhrf1 mediated AKt-mTOR axis regulates iNKT cell development.
2016-03-10 | E-GEOD-77941 | biostudies-arrayexpress
Project description:The cellular microRNA, miR-155 has been shown to be involved in lymphocyte activation and is expressed in EBV infected cells displaying type III latency gene expression but not type I latency gene expression. We show here that the elevated levels of miR-155 in type III latency cells is due to EBV gene expression and not epigenetic differences in cell lines tested and we show that expression in EBV infected cells requires a conserved AP-1 element in the miR-155 promoter. Gene expression analysis was carried out in a type I latency cell line transduced with a miR-155 expressing retrovirus. This analysis identified both miR-155 suppressed and induced cellular mRNAs and suggested that in addition to direct targeting of 3’ UTRs, miR-155 alters gene expression in part through the alteration of signal transduction pathways. 3’ UTR reporter analysis of predicted miR-155 target genes identified the transcriptional regulatory genes, BACH1, ZIC3, HIVEP2, CEBPB, ZNF652, ARID2, and SMAD5 as miR-155 targets. Western blot analysis of the most highly suppressed of these, BACH1, showed lower expression in cells transduced with a miR-155 retrovirus. Inspection of the promoters from genes regulated in EBV infected cells and in cells infected with a miR-155 retrovirus identified potential binding sequences for BACH1 and ZIC3. Together, these experiments suggest that the induction of miR-155 by EBV contributes to EBV mediated signaling in part through the modulation of transcriptional regulatory factors. Keywords: Differential expression of miR-155 vs cntl expressing cells
2008-03-18 | GSE10864 | GEO
Project description:Transcriptional profiling of iNKT gene expression in Map3k1 control and mutant mice
2016-06-01 | E-MTAB-1561 | biostudies-arrayexpress
Project description:MicroRNA-155 (miR-155) is upregulated in primary effector CD8 T cells but is expressed at low amounts in naïve cells. Anti-viral CD8 T cell responses and viral clearance were impaired in miR-155 deficient (bic-/-) mice, and this defect was intrinsic to CD8 T cells, as adoptively transferred bic-/- CD8 T cells generated greatly reduced primary and memory responses during infection. To understand the mechanism by which miR-155 regulates CD8 T cell activation, we analyzed the gene expression profiles of naive and in vitro activated wild-type and bic-/- CD8 T cells.
2013-02-26 | GSE44649 | GEO
Project description:Deletion of Uhrf1 resulted in stage 1-specific defects during iNKT cell development. To investigate the molecular mechanism, we sorted WT and Uhrf1-KO stage 1 iNKT cells and performed RNA-seq. By comparing gene expression profile, we found metabolic defects in Uhrf1-KO stage 1 iNKT cells. The expression of CD71 (Tfrc), two subunits of CD98 (Slc3a2 and Slc7a5) and Glut3 (Slc2a3) was reduced in stage 1 iNKT cells. Besides, the downstream pathways of AKT-mTOR axis were significantly reduced. Collectively, our results suggest that Uhrf1 is required for iNKT cell development by regulating the Akt-mTOR signaling pathway.
2016-03-10 | GSE77941 | GEO
Project description:The cellular microRNA, miR-155 has been shown to be involved in lymphocyte activation and is expressed in EBV infected cells displaying type III latency gene expression but not type I latency gene expression. We show here that the elevated levels of miR-155 in type III latency cells is due to EBV gene expression and not epigenetic differences in cell lines tested and we show that expression in EBV infected cells requires a conserved AP-1 element in the miR-155 promoter. Gene expression analysis was carried out in a type I latency cell line transduced with a miR-155 expressing retrovirus. This analysis identified both miR-155 suppressed and induced cellular mRNAs and suggested that in addition to direct targeting of 3’ UTRs, miR-155 alters gene expression in part through the alteration of signal transduction pathways. 3’ UTR reporter analysis of predicted miR-155 target genes identified the transcriptional regulatory genes, BACH1, ZIC3, HIVEP2, CEBPB, ZNF652, ARID2, and SMAD5 as miR-155 targets. Western blot analysis of the most highly suppressed of these, BACH1, showed lower expression in cells transduced with a miR-155 retrovirus. Inspection of the promoters from genes regulated in EBV infected cells and in cells infected with a miR-155 retrovirus identified potential binding sequences for BACH1 and ZIC3. Together, these experiments suggest that the induction of miR-155 by EBV contributes to EBV mediated signaling in part through the modulation of transcriptional regulatory factors. Keywords: Differential expression of miR-155 vs cntl expressing cells The EBV positive Burkitt's lymphoma cell line, Akata was infected with a control (pEhyg-miRCntl) or a microRNA-155 expressing (pEhyg-miR-155) retrovirus. Duplicate infections with the control retrovirus and with the miR-155 retrovirus were carried out. Control and miR-155 infection pair 1 were run on an array as well as a dye swap. Control and miR-155 infection pair 2 were similarly run on an array as well as a second array containing a dye swap.
2008-03-17 | E-GEOD-10864 | biostudies-arrayexpress
Project description:CD1d expression by thymocytes is required to select iNKT cells. When CD1d is expressed only on thymocytes (pLck-CD1d tg mice), iNKT cells are hyperresponsive to antigen stimulation suggesting that, in physiological conditions, these cells undergo functional education mediated by additional CD1d-expressing cells. Here, we investigated the mechanisms of this functional education. We find that peripheral iNKT cells from pLck-CD1d tg mice express significantly less SHP-1, a tyrosine phosphatase negatively regulating TCR signaling, than WT cells. iNKT cells from heterozygous SHP-1-mutated motheaten mice, displaying similar SHP-1 reduction as pLck-CD1d tg iNKT cells, are antigen-hyperresponsive. Restoring normal CD1d expression in pLck-CD1d tg mice normalizes SHP-1 expression and responsiveness of iNKT cells. In WT mice, iNKT cells upregulate SHP-1 and decrease responsiveness upon emigration from thymus to periphery. This depends on contacts with CD1d-expressing DCs. iNKT cell functional education is therefore controlled by DCs via tuning SHP-1 expression level in the periphery.
2013-03-01 | GSE42835 | GEO