Expression profiling of miR-142 deficient Treg cells
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ABSTRACT:
PROVIDER: PRJNA786239 | ENA |
REPOSITORIES: ENA
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Project description:miR-142 gene is specifically and abundantly expressed in hematopoietic lineages. Mice with specific deletion of this miRNA gene in Treg develop fatal autoimmunity. We used RNA-seq to detect whole transcriptome changes in miR-142 null Treg cells.
2021-12-07 | GSE190192 | GEO
Project description:Regulatory T cells (Tregs) play a fundamental role in immune tolerance via control of self-reactive effector T cells (Teffs). The development and function of the Treg lineage is critically dependent on the transcription factor Forkhead box P3 (Foxp3). Mice with a Treg-specific deletion of miRNAs, also develop a spontaneous, lethal autoimmune disease virtually indistinguishable from that seen in Foxp3-decicient mice demonstrating that miRNAs are critical for establishment of Treg-mediated peripheral tolerance. However, the set of miRNAs responsible for this functional deficiency has yet to be fully defined. Using Foxp3 ChIP-seq data we identified Mir142 as the only miRNA gene associated with a super-enhancer bound by FOXP3 suggesting that miR-142 is important for Treg function. To identify genes directly regulated by miR-142 in Tregs we profiled the changes in gene expression upon conditional deletion of miR-142 in thymically-derived Treg cells.
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Project description:MiR-142 is dynamically expressed and plays a regulatory role in hematopoiesis. Based on the simple observation that miR-142 levels are significantly lower in CD34+CD38- cells from blast crisis (BC) chronic myeloid leukemia (CML). CML patients compared with chronic phase (CP) CML patients (p=0.002), we hypothesized that miR-142 deficit plays a role in BC transformation. To test this hypothesis, we generated a miR-142 KO BCR-ABL (i.e., miR-142−/−BCR-ABL) mouse by crossing a miR-142−/− mouse with a miR-142+/+BCR-ABL mouse. While the miR-142+/+BCR-ABL mice developed and died of CP CML, the miR-142−/−BCR-ABL mice developed a BC-like phenotype in the absence of any other acquired gene mutations and died significantly sooner than miR-142+/+BCR-ABL CP controls (p=0.001). Leukemic stem cell (LSC)-enriched Lineage-Sca-1+c-Kit+ cells (LSKs) from diseased miR-142−/−BCR-ABL mice transplanted into congenic recipients, recapitulated the BC features thereby suggesting stable transformation of CP-LSCs into BC-LSCs in the miR-142 KO CML mouse. Single cell (sc) RNA-seq profiling showed that miR-142 deficit changed the cellular landscape of the miR-142−/−BCR-ABL LSKs compared with miR-142+/+BCR-ABL LSKs with expansion of myeloid-primed and loss of lymphoid-primed factions. Bulk RNA-seq analyses along with unbiased metabolomic profiling and functional metabolic assays demonstrated enhanced fatty acid β-oxidation (FAO) and oxidative phosphorylation (OxPhos) in miR-142−/−BCR-ABL LSKs vs miR-142+/+BCR-ABL LSKs. MiR-142 deficit enhanced FAO in miR-142−/−BCR-ABL LSKs by increasing the expression of CPT1A and CPT1B, that controls the cytosol-to-mitochondrial acyl-carnitine transport, a critical step in FAO. MiR-142 deficit also enhanced OxPhos in miR-142−/−BCR-ABL LSKs by increasing mitochondrial fusion and activity. As the homeostasis and activity of LSCs depend on higher levels of these oxidative metabolism processes, we then postulate that miR-142 deficit is a potentially druggable target for BC-LSCs. To this end, we developed a novel CpG-miR-142 mimic oligonucleotide (ODN; i.e., CpG-M-miR-142) that corrected the miR-142 deficit and alone or in combination with a tyrosine kinase inhibitor (TKI) significantly reduced LSC burden and prolonged survival of miR-142−/−BCR-ABL mice. The results from murine models were validated in BC CD34+CD38- primary blasts and patient-derived xenografts (PDXs). In conclusion, an acquired miR-142 deficit sufficed in transforming CP-LSCs into BC-LSCs, via enhancement of bioenergetic oxidative metabolism in absence of any additional gene mutations, and likely represent a novel therapeutic target in BC CML.
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Project description:miR-142 gene is specifically and abundantly expressed in hematopoietic cells. Mice that lack this miRNA gene develop immunodeficiency and display altered hematopoeisis. We used microarrays to detect whole transcriptome changes in miR-142 null B cells.
2015-06-15 | GSE61919 | GEO
Project description:miR-142 gene is specifically and abundantly expressed in hematopoietic cells. Mice that lack this miRNA gene develop immunodeficiency and display altered hematopoeisis. We used microarrays to detect whole transcriptome changes in miR-142 null B cells. RNA from purified WT(n=3) and miR-142 KO (n=3) CD19+ B cells was extracted and hybridized to Affymetrix GeneChips. Samples in WT and KO groups are biological replicates and were isolated in age and gender matched mice.
2015-06-15 | E-GEOD-61919 | biostudies-arrayexpress
Project description:We found miR-125a was a key regulator that stabilizes the commitment and immunoregulatory capacity of Treg cells.To gain insights into the general functional features of miR-125a-deficient Treg cells, we performed a genome-wide gene array analysis on Treg population isolated from the spleens of 6 to 8-week-old miR-125a-deficient and WT mice We sorted CD4+CD25hi Treg population from the spleens of 6 to 8-week-old miR-125a-deficient and their littermate WT mice. Cells were collected and total RNA was extracted for Affymetrix GeneChip®Mouse Genome 430 2.0 Array
2015-05-08 | E-GEOD-66608 | biostudies-arrayexpress
Project description:To gain insight into how miR-142 deficit drives a BC-like transformation, we performed RNA-seq on bone marrow (BM) Lin-Sca-1+c-Kit+ cells (LSKs) harvested from normal miR-142+/+ (wt) and miR-142−/− (miR-142 KO) mice, as well as from leukemic miR-142+/+ BCR-ABL (CP CML) and miR-142−/− BCR-ABL (BC CML) mice, two weeks after BCR-ABL induction. We then performed gene expression profiling analysis using data obtained from RNA-seq of 24 samples of LSK cells from 4 mouse strains (KO vs WT, KO CML vs CML).
2022-11-01 | GSE216794 | GEO
Project description:We found miR-125a was a key regulator that stabilizes the commitment and immunoregulatory capacity of Treg cells.To gain insights into the general functional features of miR-125a-deficient Treg cells, we performed a genome-wide gene array analysis on Treg population isolated from the spleens of 6 to 8-week-old miR-125a-deficient and WT mice
2015-05-08 | GSE66608 | GEO
Project description:The interdependence of selective cues during development of regulatory T (Treg) cells in the thymus and their suppressive function remains incompletely understood. Here we analyzed this interdependence by taking advantage of highly dynamic changes of miR-181a/b-1 during late T-cell development with very high levels of expression during thymocyte selection followed by massive downregulation in the periphery. Loss of miR-181a/b-1 resulted in inefficient de novo generation of Treg cells in the thymus, but simultaneiously permitted homeostatic expansion in the periphery in the absence of competition. Modulation of T-cell receptor (TCR) signal strength in vivo indicated that miR-181a/b-1 controlled Treg cell formation via establishing adequate signaling thresholds. Unexpectedly, miR-181a/b-1-deficient Treg cells displayed elevated suppressive capacity in vivo, in line with elevated levels of CTLA-4 protein, but not mRNA, in thymic and peripheral Treg cells. Therefore, we propose that intrathymic miR-181a/b-1 controls development of Treg cells and imposes a developmental legacy on their peripheral function.
2019-01-04 | GSE124594 | GEO
Project description:MiR-142 is upregulated in neurons in HIV and SIV encephalitis. We have created stable clones of the BE(2)M17 human neuroblastoma cell line overexpressing miR-142. Gene expression in these miR-142-expressing clones was compared to stable clones transfected with control miR-null in order to identify miR-142 targets relevant to neuronal dysfunction in HIV encephalitis.
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