Identification of miR-125b-2 target genes
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE19680 | GEO | 2009/12/29
SECONDARY ACCESSION(S): PRJNA122507
REPOSITORIES: GEO
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Project description:Although regulation of stem cell homeostasis by miRNAs is well studied, it is unclear how individual miRNAs, genomically encoded within an organized polycistron, can interact to induce an integrated phenotype. miR-99a/100, let-7 and miR-125b paralogues are encoded in two tricistrons on human chromosome 11 and 21. They are highly expressed in hematopoietic stem cells (HSCs) and acute megakaryoblastic leukemia (AMKL), an aggressive form of leukemia with poor prognosis. Integrative analysis of global gene expression profiling, miRNA target prediction and pathway architecture revealed that miR-99a/100, let-7 and miR-125b functionally converge at the combinatorial block of the TGFM-NM-2 pathway by targeting four receptor subunits and two SMAD signaling transducers. In addition, downregulation of tumor suppressor genes APC/APC2 stabilizes active M-NM-2-Catenin and enhances Wnt signaling. By switching the balance between Wnt and TGFM-NM-2 signaling the concerted action of these tricistronic miRNAs promoted sustained expansion of murine and human HSCs in vitro or in vivo, while favoring megakaryocytic differentiation. We lentivirally transduced cord blood CD34+-hematopoietic stem and progenitor cells (CB-HSPCs) to ectopically express miR-125b-2, miR-99a, let-7c or miR-99a~125b-2 and cultured them in megakaryocytic differentiation medium for 7 days.
2014-03-28 | E-GEOD-56335 | biostudies-arrayexpress
Project description:Although regulation of stem cell homeostasis by miRNAs is well studied, it is unclear how individual miRNAs, genomically encoded within an organized polycistron, can interact to induce an integrated phenotype. miR-99a/100, let-7 and miR-125b paralogues are encoded in two tricistrons on human chromosome 11 and 21. They are highly expressed in hematopoietic stem cells (HSCs) and acute megakaryoblastic leukemia (AMKL), an aggressive form of leukemia with poor prognosis. Integrative analysis of global gene expression profiling, miRNA target prediction and pathway architecture revealed that miR-99a/100, let-7 and miR-125b functionally converge at the combinatorial block of the TGFβ pathway by targeting four receptor subunits and two SMAD signaling transducers. In addition, downregulation of tumor suppressor genes APC/APC2 stabilizes active β-Catenin and enhances Wnt signaling. By switching the balance between Wnt and TGFβ signaling the concerted action of these tricistronic miRNAs promoted sustained expansion of murine and human HSCs in vitro or in vivo, while favoring megakaryocytic differentiation.
2014-03-28 | GSE56335 | GEO
Project description:The oncomir microRNA-125b (miR-125b) is up-regulated in a variety of human neoplastic blood disorders and constitutive up-regulation of miR-125b in mice can promote myeloid and B cell leukemia. We found that miR-125b promotes myeloid and B cell neoplasm by inducing tumorigenesis in hematopoietic progenitor cells. Our study demonstrates that miR-125b induces myeloid leukemia by enhancing myeloid progenitor output from stem cells as well as inducing immortality, self-renewal, and tumorigenesis in myeloid progenitors. Through functional and genetic analyses, we demonstrated that miR-125b induces myeloid and B cell leukemia by inhibiting IRF4 but through distinct mechanisms; it induces myeloid leukemia through repressing IRF4 at the mRNA level without altering the genomic DNA and induces B cell leukemia via genetic deletion of the gene encoding IRF4.
2014-06-27 | GSE58900 | GEO
Project description:The oncomir microRNA-125b (miR-125b) is up-regulated in a variety of human neoplastic blood disorders and constitutive up-regulation of miR-125b in mice can promote myeloid and B cell leukemia. We found that miR-125b promotes myeloid and B cell neoplasm by inducing tumorigenesis in hematopoietic progenitor cells. Our study demonstrates that miR-125b induces myeloid leukemia by enhancing myeloid progenitor output from stem cells as well as inducing immortality, self-renewal, and tumorigenesis in myeloid progenitors. Through functional and genetic analyses, we demonstrated that miR-125b induces myeloid and B cell leukemia by inhibiting IRF4 but through distinct mechanisms; it induces myeloid leukemia through repressing IRF4 at the mRNA level without altering the genomic DNA and induces B cell leukemia via genetic deletion of the gene encoding IRF4. The cancer myeloid (Cd11b+ sorted) and B cells (CD19+ sorted) were harvested from mice that over-express miR-125b. The genomic DNA was extracted from these cells. A total of 4 cancer samples (Two myeloid cancer samples and two B cell cancer samples) were analyzed. As control, genomic DNA from cells harvested from healthy C57bl/6 mice were harvested.
2014-06-27 | E-GEOD-58900 | biostudies-arrayexpress
Project description:Increasing evidence suggests that microRNAs may play important roles in regulating self-renewal and differentiation in mammalian stem cells (SCs). Here, we explore this issue in skin. We first characterize microRNA expression profiles of skin SCs versus their committed proliferative progenies and identify a microRNA subset associating with “stemness”. Of these, miR-125b is dramatically downregulated in early SC-progeny. We engineer an inducible mice system and show that when miR-125b is sustained in SC-progenies, tissue balance is reversibly skewed towards stemness at the expense of epidermal, oil-gland and HF differentiation. Using gain-and-loss of function in vitro, we further implicate miR-125b as a repressor of SC differentiation. In vivo, transcripts repressed upon miR-125b induction are enriched >700% for predicted miR-125b targets normally downregulated upon SC-lineage commitment. We verify some of these miR-125b targets, and show that Blimp1 and VDR in particular can account for many tissue imbalances we see when miR-125b is deregulated. We used microarrays to compare the global miRNA expression profile of P4 stage hair follicle ORS cells from DTG (K14-rtTA,TRE-miR-125b) and control littermates. Hair follicle cells were isolated from P4 Backskin (Dox since P3 for 24hrs) of DTG (K14-rtTA/TRE-miR-125b/K14-H2BGFP), TRE (TRE-miR-125b/K14-H2BGFP), KrtA (K14-rtTA/K14-H2BGFP) as following: interfollicular epidermis sheet was pealed from hair follicle & dermis after dispase treatment.The hair follicle & dermis were first digested by collagenase (Sigma). Intact hair follicles were separated from dermal cells by low speed spinning (20g). The hair follicles were then digested by Trypsin and filtered by 40 µm cell strainers. The isolated hair follicle cells were FACS sorted. During FACS, cells were first gated against CD34 (endothelial cells), CD45 (immune cells), CD114 (melanocytes) and DAPI (dead cells). ORS cells were sorted from the remaining cells as α6HiGFPHi.
2011-01-04 | E-GEOD-26395 | biostudies-arrayexpress
Project description:MiR-125b possible targets were identified after transfecting a miRNA-mimic (miR-125b) and a scramble miRNA (Negative control) in MCF7 cell line and analyzing gene expression modifications.
2013-12-02 | E-MTAB-1604 | biostudies-arrayexpress
Project description:Abnormal mitochondria metabolism and innate immune responses participate in the pathogenesis of many inflammatory disorders. The molecular events regulating mitochondrial activity to control survival and cell death in monocytes/macrophages are poorly understood. Here we show that miR-125b attenuates the activity of the mitochondrial respiratory chain through BIK silencing, and promotes the elongation of mitochondrial network through MTP18 targeting, without impacting autophagy, in the human monocytes. Proinflammatory activation is associated with a concomitant increase in miR-125b expression, decrease in BIK and MTP-18 expression, reduced oxidative phosphorylation, and enhanced mitochondrial fusion. Furthermore, expression of M1-associated transcripts as well as mitochondrial dynamics and energy metabolism are induced upon ectopic expression of miR-125b. In turn, by repressing miR-125b, mitochondrial dynamics was preserved, LPS-induced repression of BIK expression and of mitochondrial respiration were prevented, and M1 polarization of macrophages was inhibited. Altogether, our data reveal a novel role for miR-125b in controlling mitochondrial metabolism and dynamics by targeting BIK and MTP18, respectively, two novel cellular target proteins involved in maintaining the mitochondrial integrity in human monocytes. These findings not only suggest a novel function for miR-125b in regulating metabolic adaptation of monocytes to inflammation but also unravel new molecular mechanisms for its pro-apoptotic role and identify potential targets for interfering with inflammatory activation of monocytes.
2016-10-06 | GSE62693 | GEO
Project description:To better understand the mechanisms of blockage of myeloid differentiation and apoptosis and induction of proliferation by miR-125b, we proceeded to identify miR-125b target genes involved in these pathways. We analyzed the total cellular gene expression pattern by RNA-sequencing of the parental NB4 myeloid cell line and that transiently transfected with miR-125b. We generated four cDNA libraries corresponding to duplicates of miR-125b and control cells. Compare the gene expression levels in miR control transfected cells with that in miR-125b transfected NB4 cells.
2012-04-06 | E-GEOD-37061 | biostudies-arrayexpress
Project description:Here, we have screened a miRNA expression library in a pre-B cell expression system to identify miRNAs with a potential oncogenic activity in early lymphocytes. We show that miR-125b is sufficient to transform B cell precursors in vitro as defined by growth factor independence, and demonstrate that continuous expression of miR-125b is necessary to keep cells in the transformed cells. Mechanistically, we find that expression of miR-125b protects against apoptosis induced by growth factor withdrawal, and that miR-125 interferes with the differentiation of pre-B to immature B cells. In consequence, transformed cells express the pre-BCR on the cell surface, which appears to provide signals for ongoing proliferation and survival. Using microarray analysis, we identified several previously known and novel putative target genes of miR-125b in B cell precursors. To evaluate their contribution to the miR-125b-mediated phenotype, transformed cells were reconstituted with expression constructs of validated target genes. Surprisingly, we only find that reconstitution of MAP3K11 interferes with the cellular fitness of transformed cells in vitro as well as in vivo. This indicates that MAP3K11 functions as an important tumor suppressor in the context of miR-125b. Gene expression in cells expressing a control vector or a vector encoding hsa-miR-125b-1 was measured either in the presence or 24 hours after withdrawal of the growth factor IL-7. Two independent experiments were performed, using independently generated cell clones for each repetition.
2015-01-01 | E-GEOD-59994 | biostudies-arrayexpress
Project description:To better understand the mechanisms of blockage of myeloid differentiation and apoptosis and induction of proliferation by miR-125b, we preceded to identify miR-125b target genes involved in these pathways. We analyzed the total cellular gene expression pattern by RNA-sequencing of the parental 32Dclone3 myeloid cell line and that ectopically expressing miR-125b. We generated four cDNA libraries corresponding to duplicates of miR-125b and control cells. Compare the gene expression level in vector transduced 32Dclone3 cells with that in miR-125b transduced 32Dclone3 cells.
2012-04-04 | E-GEOD-37018 | biostudies-arrayexpress