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The miR-15a/16-1 and miR-15b/16-2 clusters regulate early B cell development by limiting IL-7 receptor expression II

ABSTRACT: The miR-15a/16-1 and miR-15b/16-2 clusters regulate early B cell development by limiting IL-7 receptor expression II

PROVIDER: PRJNA831866 | ENA |

REPOSITORIES: ENA

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The miR-15a/16-1 and miR-15b/16-2 clusters regulate early B cell development by limiting IL-7 receptor expression

Project description:Pleiotropic functions of miRNAs as transcriptional repressors have been reported for multiple biological processes. One prominent miRNA family is the miR-15 family, which is a well-established tumor-suppressor in B-cell chronic lymphocytic leukemia (CLL). The miR-15 family consists of three bicistronic clusters, miR-15a/16-1, miR-15b/16-2 and miR-497/195, all sharing the same seed sequence suggesting that loss one cluster can be functionally compensated by the remaining miR-15 family members. Thus, a combined deletion may be necessary to reveal its physiological function in vivo. A combined knockout of the most prominent miR-15 clusters, miR-15a/16-1 and miR-15b/16-2 in the hematopoietic system reveals a novel role of the miR-15 family in early B cell development highlighted by an increase of the pro-B cell compartment. Mechanistically, this effect is mediated by enhanced IL-7 receptor expression, which we identified as direct miR-15 target gene. Notably, elevated IL-7 receptor levels were sufficient to trigger increased activation of the STAT5 and PI3K/AKT pathways. Moreover, derepression of directly targeted cell cycle regulators such as Ccne1, Chek1 and Wee1 further facilitates G-to-S transition. Thus, by deregulating a target gene network of cell cycle and signaling mediators, loss of the miR-15 family establishes a pro-proliferative milieu manifesting in an enlarged pro-B cell pool.

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The miR-15a/16-1 and miR-15b/16-2 clusters regulate early B cell development by limiting IL-7 receptor expression II

2025-04-01 | GSE201486 | GEO

The miR-15a/16-1 and miR-15b/16-2 clusters regulate early B cell development by limiting IL-7 receptor expression

Project description:The miR-15a/16-1 and miR-15b/16-2 clusters regulate early B cell development by limiting IL-7 receptor expression

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Deletion of miR-15a/16-1 in murine germinal center B-cells.

Project description:Given the tumor suppressing function of miR-15a/16-1 cluster, we studied its role in the germinal center B-cells that give rise to most lymphoid malignancies.

2021-09-09 | PXD021323 | Pride

T cell activation decreases microRNA-15a/16 levels as a mechanism to promote MEK1-ERK1/2-Elk1 signaling for optimal proliferative capacity

Project description:While microRNAs (miRs) have been extensively studied in the context of malignancy and tumor progression, their functions in regulating T cell activation are less clear. We found reduced levels of miR-15a/16 at 3-18 h post-T cell receptor (TCR) stimulation, suggesting a role in shaping T cell activation. An inducible miR15a/16 transgenic mouse model was developed to determine how elevating miR-15a/16 levels during early stages of activation would affect T cell proliferation and to identify TCR signaling pathways regulated by this miR pair. Doxycyclin (DOX) induced expression of miR-15a/16 from 0-18 h post-TCR stimulation decreased ex vivo proliferation as well as in vivo antigen-specific proliferation. Bioinformatic and proteomic approaches were combined to identify MEK1 as a target of miR-15a/16. MEK1 targeting by miR-15a/16 was confirmed using miR mimics that decreased MEK1 containing the 3’-UTR target nucleotide sequence (UGCUGCUA) but did not decrease MEK1 containing a mutated control sequence (AAAAAAAA). Phosphorylation of downstream signaling molecules ERK1/2 and Elk1 were decreased with DOX-induced miR-15a/16 expression. In addition to MEK1, ERK1 was subsequently found to be targeted by miR-15a/16, with DOX induced miR-15a/16 reducing total ERK1 levels in T cells. These findings show that TCR stimulation reduces miR-15a/16 levels at early stages of T cell activation to facilitate increased MEK1 and ERK1, and this promotes sustained MEK1-ERK1/2-Elk1 signaling required for optimal proliferation.

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Transcriptomic profiling of HeLa cells treated with miR-15a, miR-16, miR-503 and control-miR

Project description:To have a global picture of the targets of the miR-15 family, we assessed transcriptome changes, by deep-sequencing, of HeLa cells transfected with 3 members of the miR-15 family (miR-15a, miR-16 or miR-503) or a control miRNA (cel-miR-231). We observed a very extensive overlap between the genes down-regulated by these 3 miRNAs, as expected for miRNAs belonging to the same family. transcriptmic profiles of HeLa cells treated miR-15a, miR-16, miR-503 and control-miR were generated by deep sequencing, using Illumina HiSeq2000.

2014-07-18 | E-GEOD-53279 | biostudies-arrayexpress

Transcriptomic profiling of HeLa cells treated with miR-15a, miR-16, miR-503 and control-miR

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Expression data from doxycylin-inducible miR-15a/16-1 and empty vector (EV) expression in a 13q14-\- cell line

2009-12-01 | GSE18866 | GEO

Defective Drosha Processing Contributes to Downregulation of MiR-15/-16 in Chronic Lymphocytic Leukemia.

Project description:MIR15A and MIR16-1, located in chromosomal band 13q14, are tumor suppressor miRNAs often deleted and downregulated in chronic lymphocytic leukemia (CLL). This downregulation is not only due to loss of 13q, as it occurs also in 13q+/+ CLL patients. We found that a subgroup of CLL patients has a dysregulation of miR-15 /-16 processing intermediates due to defective processing by Drosha. These patients have reduced levels of miR-15a, miR-16 and miR-15b (another member of the miR-15 family), but not of most other miRNAs. Thus, we show that modulation of miRNA maturation leads to specific downregulation of a family of tumor suppressor miRNAs in leukemic cells.

2011-12-31 | GSE30927 | GEO

Transcription profiling of human 13q14-\- cell line expressing doxycylin-inducible miR-15a/16-1 and empty vector (EV)

Project description:Reexpression of microRNAs miR-15a/16-1 in a cell line deficient for these miRs (homozygous deletion of chromosomal region 13q14) results in the downregulation of certain mRNAs. Experiment Overall Design: A doxycyclin-inducible expression vector containing miR-15a/16-1 was transfected into CLL-I83E95 cells that are deficient for those miRs. miR-expression was induced by addition of doxycyclin to the medium, and cell were harvested 48 hours later. Labeled cRNA was hybridized to microarrays and gene expression data were compared to CLL-I83U95 stably transfected with an empty vector.

2009-12-05 | E-GEOD-18866 | biostudies-arrayexpress

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