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Mouse CD4+/CD8+ thymocytes from miR-181a1/b1 KO vs WT

ABSTRACT: miR-181a1/b1, miR-181a2/b2, and miR-181c/d belong to a highly conserved family of microRNA clusters, yet their role in vivo is poorly understood. Here we show that the miR-181a1/b1 cluster is absolutely essential for NKT development and is a critical determinant of thymocyte proliferation, survival and T-cell receptor α locus rearrangement. Furthermore, while individual ablation of miR-181a2/b2 and miR-181c/d revealed no overt phenotypes, compound mutant mice lacking both miR-181a1/b1 and miR-181a2/b2 display decreased survival, reduced body weight, and abnormal B cell development. Mechanistically, we reveal that miR-181 regulates PTEN, a key tumor suppressor whose abundance determines key metabolic adaptations required to meet the biosynthetic demands of highly proliferative tissues. These results provide important insights into the physiological function of this family of microRNAs in vivo; moreover, it places miR-181 as a central regulator of the PI3K signaling pathway and cellular metabolism.

ORGANISM(S): Mus musculus

PROVIDER: GSE41090 | GEO | 2014/04/09

SECONDARY ACCESSION(S): PRJNA175759

REPOSITORIES: GEO

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Mouse CD4+/CD8+ thymocytes from miR-181a1/b1 KO vs WT

Project description:miR-181a1/b1, miR-181a2/b2, and miR-181c/d belong to a highly conserved family of microRNA clusters, yet their role in vivo is poorly understood. Here we show that the miR-181a1/b1 cluster is absolutely essential for NKT development and is a critical determinant of thymocyte proliferation, survival and T-cell receptor Î± locus rearrangement. Furthermore, while individual ablation of miR-181a2/b2 and miR-181c/d revealed no overt phenotypes, compound mutant mice lacking both miR-181a1/b1 and miR-181a2/b2 display decreased survival, reduced body weight, and abnormal B cell development. Mechanistically, we reveal that miR-181 regulates PTEN, a key tumor suppressor whose abundance determines key metabolic adaptations required to meet the biosynthetic demands of highly proliferative tissues. These results provide important insights into the physiological function of this family of microRNAs in vivo; moreover, it places miR-181 as a central regulator of the PI3K signaling pathway and cellular metabolism. Three sorted populations of double positive (DP) thymocytes from each of two conditions (WT and miR181a1/b1 -/- mice)

2014-04-09 | E-GEOD-41090 | biostudies-arrayexpress

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2008-06-12 | E-GEOD-3039 | biostudies-arrayexpress

Innate vs. adaptive lymphocyte gene expression

Project description:Three innate (B1-B, NKT, CD8aaT cells) and adaptive (B2-B, CD4T, CD8abT cells) cell-types were sorted by FACS. Three biological replicates for NKT, CD4T, CD8aaT, CD8abT cells and two biological replicates for B1 and B2 cells were generated and the expression profiles were determined using Affymetrix Mu74Av2 chip. Comparisons between the sample groups allow the identification of genes differentially expressed between the innate and adaptive cell-types. Keywords: cell type comparison, innate vs. adaptive

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Identification of miR-181 target genes and a common prognostic gene signature in AML

Project description:Increased expression levels of miR-181 family members have been shown to be associated with favorable outcome in patients with cytogenetically normal acute myeloid leukemia. Here we show that increased expression of miR-181a and miR-181b is also significantly (P < .05; Cox regression) associated with favorable overall survival in cytogenetically abnormal AML (CA-AML) patients. We further show that up-regulation of a gene signature composed of 4 potential miR-181 targets (including HOXA7, HOXA9, HOXA11, and PBX3), associated with down-regulation of miR-181 family members, is an independent predictor of adverse overall survival on multivariable testing in analysis of 183 CA-AML patients. The independent prognostic impact of this 4-homeobox-gene signature was confirmed in a validation set of 271 CA-AML patients. Furthermore, our in vitro and in vivo studies indicated that ectopic expression of miR-181b significantly promoted apoptosis and inhibited viability/proliferation of leukemic cells and delayed leukemogenesis; such effects could be reversed by forced expression of PBX3. Thus, the up-regulation of the 4 homeobox genes resulting from the down-regulation of miR-181 family members probably contribute to the poor prognosis of patients with nonfavorable CA-AML. Restoring expression of miR-181b and/or targeting the HOXA/PBX3 pathways may provide new strategies to improve survival substantially. In addition, this data set has been used to identify a common prognostic gene signature (Li Z. et al. unpublished). 65 human AML samples bearing various cytogenetic and molecular abnormalities are used to identify miR-181 target genes and a common prognostic gene signature.

2012-04-03 | E-GEOD-30258 | biostudies-arrayexpress

Identification of prognostic gene signatures in AML

Project description:Increased expression levels of miR-181 family members have been shown to be associated with favorable outcome in patients with cytogenetically normal acute myeloid leukemia. Here we show that increased expression of miR-181a and miR-181b is also significantly (P < .05; Cox regression) associated with favorable overall survival in cytogenetically abnormal AML (CA-AML) patients. We further show that up-regulation of a gene signature composed of 4 potential miR-181 targets (including HOXA7, HOXA9, HOXA11, and PBX3), associated with down-regulation of miR-181 family members, is an independent predictor of adverse overall survival on multivariable testing in analysis of 183 CA-AML patients. The independent prognostic impact of this 4-homeobox-gene signature was confirmed in a validation set of 271 CA-AML patients. Furthermore, our in vitro and in vivo studies indicated that ectopic expression of miR-181b significantly promoted apoptosis and inhibited viability/proliferation of leukemic cells and delayed leukemogenesis; such effects could be reversed by forced expression of PBX3. Thus, the up-regulation of the 4 homeobox genes resulting from the down-regulation of miR-181 family members probably contribute to the poor prognosis of patients with nonfavorable CA-AML. Restoring expression of miR-181b and/or targeting the HOXA/PBX3 pathways may provide new strategies to improve survival substantially. In addition, this data set has also been used to identify a common prognostic gene signature in human AML (Li Z. et al., unpublished). 93 human AML samples bearing various cytogenetic and molecular abnormalities are used to identify miR-181 target genes and a common prognostic gene signature.

2012-04-03 | E-GEOD-30285 | biostudies-arrayexpress

Identification of miR-181 target genes and a common prognostic gene signature in AML

2012-04-04 | GSE30258 | GEO

Identification of prognostic gene signatures in AML

Project description:Increased expression levels of miR-181 family members have been shown to be associated with favorable outcome in patients with cytogenetically normal acute myeloid leukemia. Here we show that increased expression of miR-181a and miR-181b is also significantly (P < .05; Cox regression) associated with favorable overall survival in cytogenetically abnormal AML (CA-AML) patients. We further show that up-regulation of a gene signature composed of 4 potential miR-181 targets (including HOXA7, HOXA9, HOXA11, and PBX3), associated with down-regulation of miR-181 family members, is an independent predictor of adverse overall survival on multivariable testing in analysis of 183 CA-AML patients. The independent prognostic impact of this 4-homeobox-gene signature was confirmed in a validation set of 271 CA-AML patients. Furthermore, our in vitro and in vivo studies indicated that ectopic expression of miR-181b significantly promoted apoptosis and inhibited viability/proliferation of leukemic cells and delayed leukemogenesis; such effects could be reversed by forced expression of PBX3. Thus, the up-regulation of the 4 homeobox genes resulting from the down-regulation of miR-181 family members probably contribute to the poor prognosis of patients with nonfavorable CA-AML. Restoring expression of miR-181b and/or targeting the HOXA/PBX3 pathways may provide new strategies to improve survival substantially. In addition, this data set has also been used to identify a common prognostic gene signature in human AML (Li Z. et al., unpublished).

2012-04-04 | GSE30285 | GEO

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2019-04-03 | GSE126135 | GEO

Gene expression comparison of wild-type and IL15ko thymic NKT cells

Project description:Semi-invariant natural killer T (NKT) cells are thymus-derived innate lymphocytes that modulate microbial and tumour immunity as well as autoimmune diseases. These immunoregulatory properties of NKT cells are acquired during their development. Much has been learnt regarding the molecular and cellular cues that promote NKT cell development, yet how these cells are maintained in the thymus and the periphery and how they acquire functional competence are incompletely understood. We found that IL-15 induced several Bcl-2 family survival factors in thymic and splenic NKT cells in vitro. Yet, IL15-mediated thymic and peripheral NKT cell survival critically depended on Bcl-xL expression. Additionally, IL-15 regulated thymic developmental stage 2 (ST2) to ST3 lineage progression and terminal NKT cell differentiation. Global gene expression analyses and validation revealed that IL-15 regulated Tbx21 (T-bet) expression in thymic ST3 NKT cells. The loss of IL15-dependent T-bet expression resulted in poor expression of IFN-γ and several NK cell receptors in NKT cells. Taken together, our findings reveal a critical role for IL-15 in NKT cell survival, which is mediated by Bcl-xL, and effector differentiation, which is regulated by T-bet. Gene expression was measured in NKT cells sorted from pooled thymi of wild-type (3 replicates) or IL-15 deficient (2 replicates) mice.

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