Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA242939 | ENA |
REPOSITORIES: ENA
Similar Datasets
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: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
2013-06-27 | GSE46362 | GEO
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
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
Project description:Cholangiocarcinoma (CCA) is a devastating liver cancer characterized by high aggressiveness and resistance to therapy, which results to poor prognosis. Signals imposed by oncogenic pathways, such as transforming growth factor β (TGFβ) frequently contribute to CCA development. In this study, we explored novel effectors of the TGFβ pathway in CCA by gene expression profiling. We identified the long non-coding RNA LINC00313 as a novel target gene of TGFβ signalling in CCA cells. TGFβ induced LINC00313 expression in a TβRI/Smad-dependent manner. Subcellular fractionation showed that LINC00313 is a predominantly nuclear lncRNA. By integrating RNA-seq and ATAC-seq data from LINC00313 over-expressing cells, we observed that LINC00313 regulates the expression of several genes involved in the Wnt signalling pathway. As a proof of concept, we focused on the gene encoding transcription factor 7 (TCF7), a major effector that drives transcription of Wnt-target genes. LINC00313 gain of function resulted in increased TCF7 expression, while its loss of function diminished basal or TGFβ-induced TCF7 expression levels. Interestingly, LINC00313 enhanced basal or chemically induced TCF/LEF-dependent transcriptional responses, promoted colony-forming capacities of CCA cells in vitro and accelerated tumor growth in vivo. We also report that genes associated with LINC00313 over-expression recapitulate poor prognosis human CCA associated with a reduced overall survival and KRAS mutations. To decipher the underlying molecular functions of LINC00313, we identified its interacting proteins by performing an unbiased RNA pull-down assay followed by mass spectrometry. We demonstrated that actin-like 6A (ACTL6A), a subunit of the SWI/SNF chromatin remodelling complex specifically binds to LINC00313 and impacts TCF7 expression and TCF/LEF signalling output. Thus, we propose a model whereby TGFβ induces LINC00313, in order to regulate the expression of a subset of target genes, such as TCF7 possibly in co-operation with the SWI/SNF chromatin remodelling complex, via establishing direct interaction with ACTL6A. By regulating key genes of the Wnt pathway, LINC00313 fine-tunes Wnt/TCF/LEF-dependent transcriptional responses and boosts cholangiocarcinogenesis.
2024-02-05 | E-MTAB-12879 | biostudies-arrayexpress
Project description:Cholangiocarcinoma (CCA) is a devastating liver cancer characterized by high aggressiveness and resistance to therapy, which results to poor prognosis. Signals imposed by oncogenic pathways, such as transforming growth factor β (TGFβ) frequently contribute to CCA development. In this study, we explored novel effectors of the TGFβ pathway in CCA by gene expression profiling. We identified the long non-coding RNA LINC00313 as a novel target gene of TGFβ signalling in CCA cells. TGFβ induced LINC00313 expression in a TβRI/Smad-dependent manner. Subcellular fractionation showed that LINC00313 is a predominantly nuclear lncRNA. By integrating RNA-seq and ATAC-seq data from LINC00313 over-expressing cells, we observed that LINC00313 regulates the expression of several genes involved in the Wnt signalling pathway. As a proof of concept, we focused on the gene encoding transcription factor 7 (TCF7), a major effector that drives transcription of Wnt-target genes. LINC00313 gain of function resulted in increased TCF7 expression, while its loss of function diminished basal or TGFβ-induced TCF7 expression levels. Interestingly, LINC00313 enhanced basal or chemically induced TCF/LEF-dependent transcriptional responses, promoted colony-forming capacities of CCA cells in vitro and accelerated tumor growth in vivo. We also report that genes associated with LINC00313 over-expression recapitulate poor prognosis human CCA associated with a reduced overall survival and KRAS mutations. To decipher the underlying molecular functions of LINC00313, we identified its interacting proteins by performing an unbiased RNA pull-down assay followed by mass spectrometry. We demonstrated that actin-like 6A (ACTL6A), a subunit of the SWI/SNF chromatin remodelling complex specifically binds to LINC00313 and impacts TCF7 expression and TCF/LEF signalling output. Thus, we propose a model whereby TGFβ induces LINC00313, in order to regulate the expression of a subset of target genes, such as TCF7 possibly in co-operation with the SWI/SNF chromatin remodelling complex, via establishing direct interaction with ACTL6A. By regulating key genes of the Wnt pathway, LINC00313 fine-tunes Wnt/TCF/LEF-dependent transcriptional responses and boosts cholangiocarcinogenesis.
2024-02-05 | E-MTAB-12030 | biostudies-arrayexpress
Project description:Urothelial cell carcinoma of the bladder (UCC) is a common disease characterized by FGFR3 mutation. Whilst upregulation of this oncogene occurs most frequently in low-grade non-invasive tumors, recent data reveal increased FGFR3 expression characterizes a common sub-type of invasive UCC sharing genetic similarities with lobular breast cancer. These similarities include upregulation of the FOXA1 transcription factor and reduced expression of microRNAs-99a/100. We have previously identified direct regulation of FGFR3 by these two microRNAs and now search for further targets. Using a microarray meta-database we find potential FOXA1 regulation by microRNAs-99a/100. We confirm direct targeting of the FOXA1 3’UTR by microRNAs-99a/100 and also potential indirect regulation through microRNA-485-5p/SOX5/JUN-D/FOXL1 and microRNA-486/FOXO1a. In 292 benign and malignant urothelial samples, we find an inverse correlation between the expression of FOXA1 and microRNAs-99a/100 (r=-0.33 to -0.43, p<0.05). As for FGFR3 in UCC, tumors with high FOXA1 expression have lower rates of progression than those with low expression (Log rank p=0.009). Using global gene expression and CpG methylation profiling we find genotypic consequences of FOXA1 upregulation in UCC. These are associated with regional hypomethylation and near FOXA1 binding sites, and mirror patterns previously reported in FGFR3 mutant UCC. These include gene silencing through aberrant hypermethylation (e.g. IGFBP3) and affect genes that characterize lobular breast cancer (e.g. ERBB2, XBP1). In conclusion, we have identified microRNAs-99a/100 mediate a direct relationship between FGFR3 and FOXA1, and potentially facilitate cross talk between these pathways in UCC.
2014-08-01 | GSE56037 | GEO
Project description:Epithelial homeostasis requires the precise balance of epithelial stem/progenitor proliferation and differentiation. While many of the signaling pathways that regulate epithelial stem cells have been identified, less is known about their targets or crosstalk between them. Here, we use gene expression profiling by targeted DamID to identify the stem/progenitor specific transcription and signaling factors in the Drosophila midgut. Many signaling pathway components, including ligands of most major pathways, exhibit stem/progenitor specific expression and have regulatory regions bound by both intrinsic and extrinsic transcription factors. In addition to previously identified stem/progenitor-derived ligands, we show that both the insulin-like factor Ilp6 and TNF ligand egr are specifically expressed in the stem/progenitors and regulate normal tissue homeostasis. We propose that intestinal stem cells not only integrate multiple signals but also contribute to and regulate the homeostatic signaling micro-environmental niche through the expression of autocrine and paracrine factors.
2018-11-05 | GSE101814 | GEO
Project description:Oxysterols, oxidized derivatives of cholesterol, act in breast cancer (BC) as selective estrogen receptor modulators and affect cholesterol homeostasis, drug transport, nuclear and cell receptors, and other signaling proteins. Using overlapping data from patients with early-stage estrogen receptor-positive BC—high-coverage targeted DNA sequencing (99 patients, 113 genes), mRNA sequencing (67 patients), and full miRNome by microarrays (123 patients)—we describe complex mRNA-miRNA and miRNA-miRNA interaction (correlation) networks, with validation in two carefully curated public datasets (n=538 in total) and 11 databases. The ESR1-CH25H-INSIG1-ABCA9 axis was the most prominent, being interconnected through hsa-miR-125b-5p, but also hsa-miR-99a-5p, hsa-miR-100-5p, hsa miR 143 3p, hsa-199b-5p, hsa-miR-376a-3p, and hsa-miR-376c-3p. Mutations in SC5D, CYP46A1, and its functionally linked gene set were associated with multiple differentially expressed genes. STARD5 was upregulated in patients with positive lymph node status. High expression of miR-19b-3p was weakly associated with poor survival in multiple datasets. This is the first detailed dedicated study of interactions between DNA variation and mRNA expression of oxysterol-related genes, the miRNA transcriptome, and clinical factors in BC.
2023-08-02 | GSE225292 | GEO