Dose-dependent differential mRNA target selection and regulation by let-7a-7f and miR-17-92 cluster microRNAs

Shu, Jingmin; Xia, Zhilian; Li, Lihua; Liang, Ellen; Slipek, Nicholas J.; Shen, Dawen; Foo, Jasmine; Subramanian, Subbaya; Steer, Clifford J.

doi:10.4161/rna.21998

Cited by 71 publications

(67 citation statements)

References 34 publications

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“…It has previously been shown that target gene regulation requires a specific concentration of miRNAs. 50 This explains why, in our experiments, a dose-dependent effect could be observed. These results demonstrate an allele-specific regulation of PVRL2 and IKZF3 by miR-320e and miR-326 that may be the underlying cause of their GWAS associations with lipid traits.…”

Section: Discussionsupporting

confidence: 64%

“…However, to gain more insights in the function of the SNPs, we used the well-accepted in vitro Luciferase reporter assays in combination with eQTL data, and miRNA and gene expression profiles that provide strong support for the functionality of these miRNAs. 50 This ex x x xpl p p p In conclusion, we have demonstrated that SNPs located in 3'UTRs and miRNA binding sites can affect miRNA-mediated regulation of genes involved in cardiometabolic disorders.…”

Section: Discussionmentioning

confidence: 79%

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Genetic Variations in MicroRNA-Binding Sites Affect MicroRNA-Mediated Regulation of Several Genes Associated With Cardio-metabolic Phenotypes

Ghanbari

Franco

Looper

et al. 2015

Circ Cardiovasc Genet

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Background— Genome-wide association studies enabled us to discover a large number of variants and genomic loci contributing to cardiovascular and metabolic disorders. However, because the vast majority of the identified variants are thought to merely be proxies for other functional variants, the causal mechanisms remain to be elucidated. We hypothesized that the part of the functional variants involved in deregulating cardiometabolic genes is located in microRNA (miRNA)-binding sites. Methods and Results— Using the largest genome-wide association studies available on glycemic indices, lipid traits, anthropometric measures, blood pressure, coronary artery diseases, and type 2 diabetes mellitus, we identified 11 067 variants that are associated with cardiometabolic phenotypes. Of these, 230 variants are located within miRNA-binding sites in the 3′-untranslated region of 155 cardiometabolic genes. Thirty-seven of 230 variants were found to fulfill our predefined criteria for being functional in their genomic loci. Ten variants were subsequently selected for experimental validation based on genome-wide association studies results, expression quantitative trait loci (eQTL) analyses, and coexpression of their host genes and regulatory miRNAs in relevant tissues. Luciferase reporter assays revealed an allele-specific regulation of genes hosting the variants by miRNAs. These cotransfection experiments showed that rs174545 ( FADS1 :miR-181a-2), rs1059611 ( LPL :miR-136), rs13702 ( LPL :miR-410), rs1046875 ( FN3KRP :miR-34a), rs7956 ( MKRN2 :miR-154), rs3217992 ( CDKN2B :miR-138-2-3p), and rs11735092 ( HSD17B13 :miR-375) decrease or abrogate miRNA-dependent regulation of the genes. Conversely, 2 variants, rs6857 ( PVRL2 :miR-320e) and rs907091 ( IKZF3 :miR-326), were shown to enhance the activity of miRNAs on their host genes. Conclusions— We provide evidence for a model in which polymorphisms in miRNA-binding sites can both positively and negatively affect miRNA-mediated regulation of cardiometabolic genes.

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 79%

Genetic Variations in MicroRNA-Binding Sites Affect MicroRNA-Mediated Regulation of Several Genes Associated With Cardio-metabolic Phenotypes

Ghanbari

Franco

Looper

et al. 2015

Circ Cardiovasc Genet

View full text Add to dashboard Cite

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“…We used 1% O 2 hypoxia, which is lower than in their work. Other research showed that miRs can select their target in a dose‐dependent and non‐linear fashion (Shu et al, ). However, the dose of the miR‐210 inhibitor differed from that in the Gou study, which may also explain the findings.…”

Section: Discussionmentioning

confidence: 99%

MKP‐1 is a target of miR‐210 and mediate the negative regulation of miR‐210 inhibitor on hypoxic hPASMC proliferation

Jin

Pang

Nelin

et al. 2014

Cell Biology International

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Chonic hypoxia, smooth muscle cell (SMC) proliferation and vascular remodeling are hallmark features of pathogenic pulmonary artery hypertension. MicroRNAs (miRNAs), endogenously expressed small noncoding RNAs, regulate gene expression at the post-transcriptional level. MiR-210 is considered a "master miRNA" in the control of diverse functions in hypoxic cells and tissues and has a cytoprotective function in pulmonary artery SMCs during hypoxic stress. MiR-210 is also upregulated in lung tissue of chonically hypoxic mice suffering from pulmonary hypertension. Jin et al. () showed that mice deficient in mitogen-activated protein kinase phosphatase 1 (MKP-1) had severe hypoxia-induced pulmonary hypertension, so MKP-1 may be important in the progression of hypoxic pulmonary artery hypertension. We investigated the possible interactions between miR-210 and MKP-1 and the effect on cell proliferation in hypoxic human pulmonary artery SMCs (hPASMCs). miR-210 was significantly increased in cultured hPASMCs exposed to 1% O2 hypoxia for 48 h, as was MKP-1 mRNA and protein expression. Furthermore, inhibiting miR-210 expression increased MKP-1 mRNA and protein expression in hPASMCs and decreased cell proliferation under hypoxia. Conversely, overexpressing miR-210 prevented hypoxia-induced MKP-1 expression with no effect on cell proliferation. siRNA knockdown of MKP-1 abolished the miR-210-inhibition prevention of cell proliferation under hypoxia. MKP-1 is a target of miR-210 and could mediate the negative regulation of miR-210 inhibition on hypoxic hPASMCs.

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“…Microvesicles carry and transfer genetic material to target cells, which has been confirmed in many studies. Among these, microRNA‐17‐92 clusters carried by MVs were considered to affect the viability of target cells in a dose‐dependent manner, after entering the target cells . EMVs carrying microRNA‐19b into perivascular adipose tissue were considered to promote the secretion of inflammatory cytokines and macrophage infiltration in adipose tissues .…”

Section: Biological Effects Of Active Moleculesmentioning

confidence: 99%

The role of microvesicles and its active molecules in regulating cellular biology

Tan

Miao

et al. 2019

J Cellular Molecular Medi

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Cell‐derived microvesicles are membrane vesicles produced by the outward budding of the plasma membrane and released by almost all types of cells. These have been considered as another mechanism of intercellular communication, because they carry active molecules, such as proteins, lipids and nucleic acids. Furthermore, these are present in circulating fluids, such as blood and urine, and are closely correlated to the progression of pathophysiological conditions in many diseases. Recent studies have revealed that microvesicles have a dual effect of damage and protection of receptor cells. However, the nature of the active molecules involved in this effect remains unclear. The present study mainly emphasized the mechanism of microvesicles and the active molecules mediating the different biological effects of receptor cells by affecting autophagy, apoptosis and inflammation pathways. The effective ways of blocking microvesicles and its active molecules in mediating cell damage when microvesicles exert harmful effects were also discussed.

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Dose-dependent differential mRNA target selection and regulation by let-7a-7f and miR-17-92 cluster microRNAs

Abstract: (2012) Dose-dependent differential mRNA target selection and regulation by let-7a-7f and miR-17-92 cluster microRNAs, RNA Biology, 9

Cited by 71 publications

References 34 publications

Genetic Variations in MicroRNA-Binding Sites Affect MicroRNA-Mediated Regulation of Several Genes Associated With Cardio-metabolic Phenotypes

Genetic Variations in MicroRNA-Binding Sites Affect MicroRNA-Mediated Regulation of Several Genes Associated With Cardio-metabolic Phenotypes

MKP‐1 is a target of miR‐210 and mediate the negative regulation of miR‐210 inhibitor on hypoxic hPASMC proliferation

The role of microvesicles and its active molecules in regulating cellular biology

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