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MiR-99a/100~125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between TGFM-NM-2 and Wnt signaling

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

SUBMITTER: Jan-Henning Klusmann

PROVIDER: E-GEOD-56335 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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miR-99a/100~125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between TGFβ and Wnt signaling

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

Expression data from ETV6-RUNX1-positive Reh leukemic cells after overexpression of miR-125b, miR-100 and miR-99a levels in different combinations

Project description:Combined overexpression of miR-125b with miR-99a and/or miR-100 induced VCR resistance in ETV6-RUNX1-positive leukemic cells Reh. We used microarrays to detail the global changes in gene expression of Reh cells upon enforced expression of miR-125 per se compared with combination of overexpression of miR-125b, miR-100 and/or miR-99a MiR-99a and/or miR-100 were transiently overexpressed in stable miR-125b-expressing and stable scrambled miR-control-expressing Reh cells. Cellular resistance to VCR was determined by MTT assay after incubating the cells with 9 ng/mL VCR for 3 days. Changes in the gene expression pattern of Reh cells induced by miRNAs overexpression were measured using Affymetrix Arrays.

2013-06-27 | E-GEOD-46362 | biostudies-arrayexpress

Expression data from ETV6-RUNX1-positive Reh leukemic cells after overexpression of miR-125b, miR-100 and miR-99a levels in different combinations

2013-06-27 | GSE46362 | GEO

Expression data after miR-99a transfection in C4-2 prostate cancer cells

Project description:MicroRNAs (miRNAs) have been globally profiled in cancers but there tends to be poor agreement between studies including in the same cancers. Additionally, few putative miRNA targets have been validated. To overcome the lack of reproducibility, we profiled miRNAs by next generation sequencing and locked nucleic acid miRNA microarrays, and we verified concordant changes by quantitative RT-PCR. Notably, miR-125b and the miR-99 family members miR-99a, -99b, -100 were down-regulated in all assays in advanced prostate cancer cell lines relative to the parental cell lines from which they were derived. All four miRNAs were also down-regulated in human prostate tumor tissue compared to normal prostate. Transfection of miR-99a, -99b or -100 inhibited the growth of prostate cancer cells and decreased the expression of prostate-specific antigen (PSA), suggesting potential roles as tumor suppressors in this setting. To identify targets of these miRNAs, we combined computational prediction of potential targets with experimental validation by microarray and polyribosomal loading analysis. Three direct targets of the miR-99 family that were validated in this manner were the chromatin remodeling factors SMARCA5 and SMARCD1 and the growth regulatory kinase mTOR. We determined that PSA is post-transcriptionally regulated by the miR-99 family members at least partially by repression of SMARCA5. Together, our findings suggest key functions and targets of miR-99 family members in prostate cancer suppression and prognosis. C4-2 cells were transfected with miR-99a and harvested after 48hr. si-GL2 was used as control.

2010-12-29 | E-GEOD-26332 | biostudies-arrayexpress

miRNA expression in human tracheal smooth muscle

Project description:We surveyed miRNA expression in intact airway smooth muscle tissue to evaluate candidate miRNA for further studies. We found 60 miRNA expressed at a detectable level in all four donors and another 118 miRNA expressed in three of the four donors. There were 18 miRNAs with expression levels > 2-fold above normalized expression values. These consisted of 12 described human miRNA, including let-7c, miR-16, -23b, -24, -26a, -125b, -143, -145, -200c and -205; 3 mouse miRNAs including miR-99a, -140* and -370; and 3 novel miRNA termed abi-13143, -13232 and -13268.

2009-07-22 | GSE16586 | GEO

Down modulation of miR-99a/let-7c/miR-125b miRNA cluster predicts clinical outcome in patients with unresected malignant pleural mesothelioma

Project description:Malignant pleural mesothelioma (MPM) is an aggressive tumor with a dismal overall survival (OS) and to date few molecular markers are available to guide patient management. This study aimed to identify a prognostic miRNA signature in MPM patients who did not undergo tumor resection. Whole miRNA profiling using a microarray platform was performed on 26 unresected MPM with distinct clinical outcome: 15 patients had aggressive disease (OS<12 months) and 11 patients indolent disease (OS>36 months). Three prognostic miRNAs (mir-99a, let-7c and miR-125b) encoded at the same cluster (21q21) were selected for further validation and tested on publicly available miRNA sequencing data (TCGA) from 72 MPM patients with survival data. A risk model was built based on these 3 miRNAs that was validated by quantitative PCR in an independent set of 30 MPM patients. High risk patients had shorter median OS (7.6 months) as compared with low-risk patients (median not reached). In the multivariate Cox model, a high risk score was an independently associated with shorter OS (HR=3.14; 95% CI, 1.18–8.34; P=0.022). Our study identified that the downregulation of the miR-99a/let-7/miR-125b miRNA cluster predicts poor outcome in unresected MPM.

2017-07-28 | GSE92636 | GEO

Expression data after miR-99a transfection in C4-2 prostate cancer cells

2010-12-29 | GSE26332 | GEO

miRNA Alterations in Lung Macrophages after Nitrogen Mustard Exposure

Project description:Activated macrophages have been implicated in lung injury and fibrosis induced by the cytotoxic alkylating agent, nitrogen mustard (NM). Herein, we determined if macrophage activation is associated with altered miRNA expression. Treatment of rats with NM (0.125 mg/kg, i.t.) resulted in significant increases in miRNA expression 1, 3, 7, and 28 d post exposure as determined by PCR array analysis of miRNAs (miR)s involved in inflammation and fibrosis. Expression of many miRNAs were significantly increased at multiple time-points while one miRNA was uniquely expressed 1 d post-NM, one at 3 d, two at 7 d, and five at 28 d. An IPA Core Analysis of predicted mRNA targets of differentially expressed miRNAs identified significant enrichment of Diseases and Functions related to cell cycle arrest, apoptosis, cell movement, cell adhesion, and inflammation 1 d and 28 d post NM. Significant enrichment of pathways related to lipid metabolism is consistent with previous studies reporting the development of macrophage foam cells after NM exposure. miRNA-mRNA interaction network analysis identified highly connected miRNAs representing key upstream regulators of mRNAs involved in significantly enriched Diseases and Functions including miR-34c-5p and miR-27a-3p at 1 d post NM and miR-125b-5p, miR-16-5p, miR-30c-5p, miR-19b-3p, and miR-148b-3p at 28 d post NM. Collectively, these data show that NM promotes histone remodeling and alterations in miRNA expression linked to lung macrophage responses during inflammatory injury and fibrosis.

2021-04-19 | GSE172290 | GEO

MicroRNA profiling and discovery by deep sequencing cord blood from Down syndrome fetuses

Project description:To investigate the expression characteristic of miRNAs during the development of Down syndrome (DS) fetuses and to identify whether another miRNA gene resides in the Hsa21, we employed high-throughput Solexa sequencing technology to comprehensively characterize the miRNA expression profiles of both DS and normal fetal cord blood mononuclear cells (CBMCs). In total, 200 of 395 identified miRNAs were significantly differentially expressed (fold change > 2.0 and P-value < 0.001) and 2 of 181 candidate novel miRNAs were identified as residing within the "Down syndrome critical region" of human chromosome 21 (chr21q22.2-22.3). Additionally, 7 of 14 Hsa21-derived miRNAs genes were detected that three miRNAs (hsa-miR-802, miR-3648, miR-3687) were up-regulated more than 50% and four miRNAs (hsa-miR-99a, let-7c, miR-125b-2, miR-155) were down-regulated in the DS fetal CBMCs compared with the control. Bioinformatics analyses revealed that abnormally expressed miRNAs were major associated with the regulation of transcription, gene expression, cellular biosynthetic process, macromolecule biosynthetic process and nucleic acid metabolic process. The data obtained in our study provides a considerable insight into understanding the expression characteristic of miRNAs in the DS fetal hemopoietic system and the differentially expressed miRNAs may be involved in the hemopoietic abnormalities and the immune defects of DS fetus and newborns.

2015-07-17 | GSE39436 | GEO

miR-99a let7c cluster

Project description:To investigate the function of miR99a/let-7c miRNAs during cardiomyogenesis, we decided to perturb their expression using transgenic mES cell lines the corresponding precursors (pre-miRNA) of the two miRNAs. We used the ROSA-TET system (EB3 tet off), in which the transgene is inserted in Rosa26 locus by Cre recombinase. We generated three different clones both miRNAs let-7c/miR-99a and those only one miRNA, namely the let-7cdeletedmiR-99a and the miR-99adeletedlet-7c.

2013-07-01 | E-MEXP-3748 | biostudies-arrayexpress

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