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MiR-17/20a mitigates interstitial fibrosis by repressing Frmd6 expression in renal epithelia [PAR-CLIP]

ABSTRACT: In this study, we evaluated genetic mouse models of inducible renal epithelia-specific miR-17~92 loss-of-function and gain-of-function using unilateral ureteral obstruction. We utilized PAR-CLIP in HK2 cells to identify miR-17/-20a targets, which we subsequently validated in vitro. We examined expression of a novel miR-17/-20a target in human nephrectomy samples with varying degrees of fibrosis. We identify an activator of Hippo signaling, FERM domain-containing protein 6 (FRMD6, also known as Willin), as a novel miR-17/20a target. Frmd6 is upregulated in tubular epithelium of obstructed kidneys that lack miR-17~92, along with increased phosphorylation of Smad3 and STAT3, two known miR-17~92 profibrotic targets. Frmd6 overexpression is sufficient to result in elevated secretion of the extracellular matrix component collagen III in vitro. Finally, we demonstrate that FRMD6 expression is associated with collagen III expression in human nephrectomy samples.Our findings demonstrate that the miR-17~92 cluster in renal epithelia functions in an anti-fibrotic manner by regulating multiple pro-fibrotic pathways. We also identify Frmd6 as a novel miR-17/20a target in renal epithelia, which may drive renal fibrosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE254785 | GEO | 2025/01/30

REPOSITORIES: GEO

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miR-17/20a mitigates interstitial fibrosis by repressing Frmd6 expression in renal epithelia [miRNA-seq]

Project description:In this study, we evaluated genetic mouse models of inducible renal epithelia-specific miR-17~92 loss-of-function and gain-of-function using unilateral ureteral obstruction. We utilized PAR-CLIP in HK2 cells to identify miR-17/-20a targets, which we subsequently validated in vitro. We examined expression of a novel miR-17/-20a target in human nephrectomy samples with varying degrees of fibrosis. We identify an activator of Hippo signaling, FERM domain-containing protein 6 (FRMD6, also known as Willin), as a novel miR-17/20a target. Frmd6 is upregulated in tubular epithelium of obstructed kidneys that lack miR-17~92, along with increased phosphorylation of Smad3 and STAT3, two known miR-17~92 profibrotic targets. Frmd6 overexpression is sufficient to result in elevated secretion of the extracellular matrix component collagen III in vitro. Finally, we demonstrate that FRMD6 expression is associated with collagen III expression in human nephrectomy samples.Our findings demonstrate that the miR-17~92 cluster in renal epithelia functions in an anti-fibrotic manner by regulating multiple pro-fibrotic pathways. We also identify Frmd6 as a novel miR-17/20a target in renal epithelia, which may drive renal fibrosis.

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miR-17/20a mitigates interstitial fibrosis by repressing Frmd6 expression in renal epithelia [RNA-seq]

2025-01-30 | GSE254782 | GEO

A global transcriptome analysis of human epidermal keratinocytes upon overexpression of microRNA-19a or microRNA-19b or microRNA-20a

Project description:Several members from microRNA 17-92 cluster, i.e. miR-19a, miR-19b and miR-20a, were found up-regulated in human epidermal keratinocytes at wound-edges compared to the intact skin; however their biological role in keratinocytes during wound repair has not been studied. To study the genes regulated by miR-19a, miR-19b and miR-20a, we transfected miRNA specific mimics, i.e. pre-miR-19a, pre-miR-19b or pre-miR-20a into human primary epidermal keratinocytes to overexpress them. We performed a global transcriptome analysis of keratinocytes upon overexpression of miR-19a or miR-19b or miR-20a using Affymetrix arrays.

2017-02-15 | GSE93110 | GEO

miR-17/20a mitigates interstitial fibrosis by repressing Frmd6 expression in renal epithelia

Project description:miR-17/20a mitigates interstitial fibrosis by repressing Frmd6 expression in renal epithelia

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Members of the microRNA-17-92 cluster exhibit a cell intrinsic anti-angiogenic function in endothelial cells

Project description:MicroRNAs are endogenously expressed small non-coding RNAs that regulate gene expression on the posttranscriptional level. The miR-17-92 cluster (encoding miR-17, -18a, -19a/b, -20a and miR-92a) is highly expressed in tumor cells and is up-regulated by ischemia. Whereas miR-92a was recently identified as negative regulator of angiogenesis, the specific functions of the other members of the cluster are less clear. Here we demonstrate that overexpression of miR-17, -18a, -19a and -20a significantly inhibited 3D spheroid sprouting in vitro, whereas inhibition of miR-17, -18a and -20a augmented endothelial cell (EC) sprout formation. Inhibition of miR-17 and miR-20a in vivo using antagomirs significantly increased the number of perfused vessels in matrigel plugs, whereas antagomirs, that specifically target miR-18a and miR-19a were less effective. However, systemic inhibition of miR-17/20 did not affect tumor angiogenesis. Further mechanistic studies showed that miR-17/20 targets several pro-angiogenic genes. Specifically, Janus kinase 1 (Jak1) was shown to be a direct target of miR-17. In summary, we show that miR-17/20 exhibit a cell intrinsic anti-angiogenic activity in ECs. Inhibition of miR-17/20 specifically augmented neovascularization of matrigel plugs, but did not affect tumor angiogenesis indicating a context-dependent regulation of angiogenesis by miR-17/20 in vivo.

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Comparative gene expression profiling of cutaneous B cell lymphomas

Project description:The oncogenic microRNA 17-92 cluster is involved in the lymphomagenesis of nodal and systemic B cell lymphomas, but has not been studied so far in primary cutaneous B cell lymphomas. We performed the quantitative analysis of miR-17-92 cluster and its paralogs miR-106a-363 and miR-106b-25 in 22 primary cutaneous diffuse large B-cell lymphomas-leg type (PCLBCL-LT) and 22 primary cutaneous follicle center lymphomas (PCFCL). Mir-20a and miR-106a were overexpressed in PCLBCL-LT compared to PCFCL. Multivariate Cox analysis showed that higher miR-20a and miR-20b were associated with poorer disease-free survival and poorer overall survival, independently of histological type. Gene expression profiling showed underexpression of 8 candidate target genes of miR-20a, miR-20b and miR-106a in PCLBCL-LT compared to PCFCL. Among the candidate target genes, PTEN, NCOA3 and CAPRIN2 were confirmed to be underexpressed in PCLBCL-LT using quantitative RT-PCR of laser-microdissected tumor cells. In multivariate Cox analysis, lower PTEN mRNA expression level was associated with poorer disease-free survival, independently of the histological type. Altogether, this molecular and bioinformatics study of patients’ skin biopsy samples showed that the oncogenic miR-17-92 cluster is involved in cutaneous B cell lymphoma progression, and that the down-regulation of its target gene PTEN is associated with poorer disease-free survival.

2016-12-31 | GSE55833 | GEO

Yuan- microRNAs upregulated in Ep300-overexpressing mouse heart

Project description:Objective: To characterize downstream effectors of p300 acetyltransferase in the myocardium. Background: Acetyltransferase p300 is a central driver of the hypertrophic response to increased workload, but its biological targets and downstream effectors are incompletely known. Methods and Results: Mice expressing a myocyte-restricted transgene encoding acetyltransferase p300, previously shown to develop spontaneous hypertrophy, were observed to undergo robust compensatory blood vessel growth together with increased angiogenic gene expression. Chromatin immunoprecipitation demonstrated binding of p300 to the enhancers of the angiogenic regulators Angpt1 and Egln3. Interestingly, p300 overexpression in vivo was also associated with relative upregulation of several members of the anti-angiogenic miR-17~92 cluster in vivo. Confirming this finding, both miR-17-3p and miR-20a were upregulated in neonatal rat ventricular myocytes following adenoviral transduction of p300. Relative expression of most members of the 17~92 cluster was similar in all 4 cardiac chambers and in other organs, however, significant downregulation of miR-17-3p and miR-20a occurred between 1 and 8 months of age in both wt and tg mice. The decline in expression of these microRNAs was associated with increased expression of VEGFA, a validated miR-20a target. In addition, miR-20a was demonstrated to directly repress p300 expression through a consensus binding site in the p300 3’UTR. In vivo transduction of p300 resulted in repression both of p300 and of p300-induced angiogenic transcripts. Conclusion: p300 drives an angiogenic transcription program during hypertrophy that is fine-tuned in part through direct repression of p300 by miR-20a.

2013-09-30 | GSE50843 | GEO

Yuan- microRNAs upregulated in Ep300-overexpressing mouse heart

2013-09-30 | E-GEOD-50843 | biostudies-arrayexpress

Members of the microRNA-17-92 cluster exhibit a cell intrinsic anti-angiogenic function in endothelial cells

2010-03-23 | E-GEOD-20745 | biostudies-arrayexpress

Differential regulation of aggressive features in melanoma cells by members of the miR-17-92 complex

Project description:The various roles of microRNAs (miRNAs) in controlling the phenotype of cancer cells are the focus of contemporary research efforts. We have recently shown that miR-17 directly targets the ADAR1 gene and thereby enhances melanoma cell aggressiveness. miR-17 and miR-20a belong to the miR-17/92 complex, and their mature forms are identical except for two non-seed nucleotides. Nevertheless, here we show that these two miRNAs carry markedly different effects on melanoma cells. A strong positive correlation was observed between the expression of miR-17 and miR-20a among various melanoma cultures. Luciferase assays showed that miR-17 but not miR-20a directly targets the 3' untranslated region of the ADAR1 gene. Ectopic expression of these miRNAs in melanoma cells differentially alters the expression of five exemplar TargetScan-predicted target genes ADAR1, ITGB8, TGFBR2, MMP2 and VEGF-A. Whole genome expression microarrays confirm a markedly differential effect on the transcriptome. Functionally, over-expression of miR-20a but not of miR-17 in melanoma cells inhibits net proliferation in-vitro. The differential functional effect was observed following ectopic expression of the mature miRNA or of the pre-miRNA sequences. This suggests that the two non-seed nucleotides dictate target sequence recognition and overall functional relevance. These miRNAs are clearly not redundant in melanoma cell biology.

2014-12-31 | GSE57158 | GEO

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