Ontology highlight
ABSTRACT:
PROVIDER: PRJNA407603 | ENA |
REPOSITORIES: ENA
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Project description:The microRNAs encoded by the miR-17~92 polycistron are commonly overexpressed in cancer and orchestrate a wide range of oncogenic functions. Here, we identify a novel mechanism for miR-17~92 oncogenic function through the disruption of endogenous miRNA processing. We show that upon oncogenic overexpression of the miR-17~92 primary transcript (pri-miR-17~92), the Microprocessor complex remains associated with partially processed intermediates that aberrantly accumulate. These intermediates reflect a series of hierarchical and conserved steps in the early processing of the pri-miR-17~92 transcript. Encumbrance of the Microprocessor by miR-17~92 intermediates leads to the broad, but selective, downregulation of co-expressed polycistronic miRNAs, including miRNAs derived from tumour suppressive miR-34b/c, and from the Dlk1-Dio3 polycistrons. We propose that the newly identified steps of polycistronic miR-17~92 biogenesis contribute to the oncogenic re-wiring of gene regulation networks. Our results reveal new functional paradigms for polycistronic miRNAs in cancer.
2019-05-20 | GSE130282 | GEO
Project description:The precise control of miR-17~92 microRNA (miRNA) is essential for normal development and overexpression of certain miRNAs from this cluster is oncogenic. Here we find the relative expression of the six miRNAs processed from the primary (pri-miR-17~92) transcript is dynamically regulated during embryonic stem cell differentiation. We identify a new miRNA biogenesis intermediate, termed ‘progenitor-miRNA’ (pro-miRNA), that is an efficient substrate for Microprocessor. An autoinhibitory 5’ RNA fragment is cleaved to generate pro-miRNA and selectively license Microprocessor-mediated production of pre-miR-17, -18a, -19a, 20a, and -19b. Using genetic, biochemical, and structural methods we define two complementary cis-regulatory repression domains required for the formation of this inhibitory RNA conformation. We find the endonuclease CPSF3 (CPSF73), and the Spliceosome-associated ISY1 are required for pro-miRNA biogenesis and expression of all miRNAs within the cluster except miR-92. Thus, developmentally regulated generation of pro-miRNA explains the posttranscriptional control of miR-17~92 expression in development. Illumina RNAseq in WT, dgcr8-/- and dicer-/- mESCs and small RNA seq in WT mESCs
2015-05-11 | E-GEOD-68699 | biostudies-arrayexpress
Project description:The precise control of miR-17~92 microRNA (miRNA) is essential for normal development and overexpression of certain miRNAs from this cluster is oncogenic. Here we find the relative expression of the six miRNAs processed from the primary (pri-miR-17~92) transcript is dynamically regulated during embryonic stem cell differentiation. We identify a new miRNA biogenesis intermediate, termed ‘progenitor-miRNA’ (pro-miRNA), that is an efficient substrate for Microprocessor. An autoinhibitory 5’ RNA fragment is cleaved to generate pro-miRNA and selectively license Microprocessor-mediated production of pre-miR-17, -18a, -19a, 20a, and -19b. Using genetic, biochemical, and structural methods we define two complementary cis-regulatory repression domains required for the formation of this inhibitory RNA conformation. We find the endonuclease CPSF3 (CPSF73), and the Spliceosome-associated ISY1 are required for pro-miRNA biogenesis and expression of all miRNAs within the cluster except miR-92. Thus, developmentally regulated generation of pro-miRNA explains the posttranscriptional control of miR-17~92 expression in development.
2015-05-11 | GSE68699 | GEO
Project description:Estrogen receptor alpha (ERα) is a nuclear receptor linked to progression of the majority of human breast cancers. Following activation ERα regulates the transcription of target genes via DNA binding. Through a genome wide approach we have identified a subset of microRNAs (miRNAs or miRs) modulated by ERα. Among them, miRNAs encoded from 2 paralogous clusters, miR-17-92 and miR-106a-363, were up-regulated. In addition, increased expression of miR-424, miR-542-3p and miR-450, located within the same genomic region and down-regulation of miR-181 family members were observed during the estrogenic response. We observed that ERα alone is sufficient for sustained transcription of miR-17-92 and we show that levels of this cluster increase earlier than miRNAs encoded by it, implicating post-transcriptional regulation. Since miR-17-92 a pri-miRNA, is immediately cleaved by DROSHA to pre-miR-18a, this regulation occurs during the formation of the mature molecule from the precursor. Moreover, pre-miR-18a was significantly up-regulated in ERα-positive breast cancers compared to ERα-negative breast cancers. We also demonstrate that the miRNAs belonging to these paralogous clusters target and down-regulate ERα, while a subset of cluster-derived miRNAs inhibit protein translation of its major oncogenic transcriptional p160 co-activator by targeting AIB1 revealing a negative autoregulatory feedback loop. This pathway adds to the highly regulated cellular response to estrogen that fine tunes ERα transcriptional activity and cell proliferation.
2009-05-01 | GSE14685 | GEO
Project description:XPO5 mediates nuclear export of miRNA hairpin precursors in a RanGTP-dependent manner. However, the requirement of XPO5 for global miRNA biogenesis and mammalian development and XPO5-associated RNA species are not determined. Here we show that XPO5 is required for mouse embryonic development and morphogenesis of skin and brain. Loss of XPO5 compromises the biogenesis of most miRNAs and that leads to severe developmental defects. Surprisingly, XPO5 not only associates with miRNA hairpin precursors but also pervasively binds to double-stranded RNA (dsRNA) regions found in many cellular RNAs and some clustered pri-miRNAs. The binding of XPO5 to miR-17~92 pri-miRNAs is RanGTP-independent. Pre-incubation with XPO5 enhances the processing efficiency of the DROSHA/DGCR8 microprocessor. Together, our studies demonstrate the requirement of XPO5 for miRNA biogenesis and mouse development, reveal an unexpected role of XPO5 for recognizing and facilitating the nuclear cleavage of clustered pri-miRNAs and identify numerous cellular RNAs as novel XPO5 subtracts.
2020-02-19 | GSE111964 | GEO
Project description:A network of gene regulatory factors such as transcription factors and microRNAs establish and maintain the gene expression pattern during hematopoiesis. In this network transcription factors regulate each other and are involved in regulatory loops with microRNAs.The microRNA cluster miR-17-92 is located within the MIR17HG gene and encodes for six mature microRNAs. It is important for hematopoietic differentiation and plays a central role in malignant disease. However, the transcription factors downstream of miR-17-92 are largely elusive and the transcriptional regulation of miR-17-92 is not fully understood. Here we show that miR-17-92 forms a regulatory loop with the transcription factor TAL1. The miR-17-92 cluster inhibits expression of TAL1 and indirectly leads to decreased stability of the TAL1 transcriptional complex. We found that TAL1 and its heterodimerization partner E47 regulate miR-17-92 transcriptionally. Furthermore, miR-17-92 negatively influences erythroid differentiation, a process that depends on gene activation by the TAL1 complex. Our data give example of how transcription factor activity is fine-tuned during normal hematopoiesis. We postulate that disturbance of the regulatory loop between TAL1 and the miR-17-92 cluster could be an important step in cancer development and progression.
2021-09-09 | PXD018052 | Pride
Project description:Knockout of the ubiquitously expressed microRNA-17~92 cluster in mice produces a lethal developmental lung defect. We validated the equally widely expressed pro-apoptotic Bim gene as joint target of miR-17~92 cluster members. To study the contribution of miR-17~92:Bim interaction to miR-17~92 overall function, we set up a system of conditional mutagenesis of the Bim 3’UTR. Blocking miR-17~92:Bim interaction early in development phenocopied the lethal lung phenotype of miR-17~92 ablation. Thus, despite hundreds of overall predicted targets vital miRNA functions can be mediated by a single target gene.
2019-11-10 | GSE123671 | GEO
Project description:Estrogen receptor alpha (ERα) is a nuclear receptor linked to progression of the majority of human breast cancers. Following activation ERα regulates the transcription of target genes via DNA binding. Through a genome wide approach we have identified a subset of microRNAs (miRNAs or miRs) modulated by ERα. Among them, miRNAs encoded from 2 paralogous clusters, miR-17-92 and miR-106a-363, were up-regulated. In addition, increased expression of miR-424, miR-542-3p and miR-450, located within the same genomic region and down-regulation of miR-181 family members were observed during the estrogenic response. We observed that ERα alone is sufficient for sustained transcription of miR-17-92 and we show that levels of this cluster increase earlier than miRNAs encoded by it, implicating post-transcriptional regulation. Since miR-17-92 a pri-miRNA, is immediately cleaved by DROSHA to pre-miR-18a, this regulation occurs during the formation of the mature molecule from the precursor. Moreover, pre-miR-18a was significantly up-regulated in ERα-positive breast cancers compared to ERα-negative breast cancers. We also demonstrate that the miRNAs belonging to these paralogous clusters target and down-regulate ERα, while a subset of cluster-derived miRNAs inhibit protein translation of its major oncogenic transcriptional p160 co-activator by targeting AIB1 revealing a negative autoregulatory feedback loop. This pathway adds to the highly regulated cellular response to estrogen that fine tunes ERα transcriptional activity and cell proliferation. 4 time points (0hr,3hr,6hr,12hr) and 4 treatments (TO,JP,TO+TET,JP13+TET) x 3 biological replicates of each condition = 24 arrays
2010-06-25 | E-GEOD-14685 | biostudies-arrayexpress
Project description:Adult beta cells in the pancreas are the sole source of insulin in our body. Beta cell loss or increased demand for insulin, impose metabolic challenges because adult beta cells are generally quiescent and infrequently re-enter the cell division cycle. miR-17-92/106b is a family of proto-oncogene microRNAs, that regulate proliferation in normal tissues and in cancer. Here, we employ mouse genetics to demonstrate a critical role for miR-17-92/106b in glucose homeostasis and in controlling insulin secretion. Mass spectrometry analysis was performed on miR-17-92LoxP/LoxP;106-25-/- MEF lysate, without or with CRE-Adenovirus. miR-17-92LoxP/LoxP;106-25+/+ MEFs with GFP-Adenovirus served as controls. We demonstrate that miR-17-92/106b regulate the adult beta cell mitotic checkpoint and that miR-17-92/106b deficiency results in reduction in beta cell mass in-vivo. Furthermore, protein kinase A (PKA) is a new relevant molecular pathway downstream of miR-17-92/106b in control of adult beta cell division and glucose homeostasis. Therefore, contributes to the understanding of proto-oncogene miRNAs in the normal, untransformed endocrine pancreas, and illustrates new genetic means for regulation of beta cell mitosis and function by non-coding RNAs.
2019-06-17 | PXD012610 | Pride
Project description:Gain of chromosome arm 13q is one of the most prevalent DNA copy number alterations associated with colorectal adenoma-to-carcinoma progression. The oncogenic miR-17-92 cluster, located at 13q, was found to be overexpressed in colorectal cancer and in adenomas harboring 13q gain. However, to what extent overexpression of this group of microRNAs actually drives progression to cancer remains to be resolved. Therefore, we aimed to clarify the role of miR-17-92 cluster in the progression from colorectal adenoma to carcinoma.
In human colorectal adenoma organoids without 13q gain, the miR-17-92 cluster was overexpressed and downstream effects on mRNA expression investigated, along with functional effects in vitro and in vivo.
Comparison of mRNA sequencing results of organoids overexpressing miR-17-92 and cultures transduced with control vector, revealed a miR-17-92 expression signature. This signature appeared to be enriched in an independent series of colorectal cancers and adenomas tissues with 13q gain, confirming that miR-17-92 expression is associated with malignant progression. However, an increase in proliferation rate was not observed in miR-17-92 overexpressing adenoma organoids in vitro. In addition, subcutaneous injection of these organoids in immunodeficient mice was insufficient to cause tumor outgrowth.
Transfecting miR-17-92 cluster in human colon adenoma organoids induces an expression signature that proved to be enriched in both adenomas with 13q gain and in colorectal cancers, supporting its role as a driver of 13q gain. However, overexpression of miR-17-92 alone is not sufficient to transform colorectal adenoma cells into a malignant phenotype.
| EGAS00001005949 | EGA