Complexity of Murine Cardiomyocyte miRNA Biogenesis, Sequence Variant Expression and Function

Humphreys, David T.; Hynes, Carly J.; Patel, Hardip R.; Wei, Grace; Cannon, Leah; Fatkin, Diane; Suter, Catherine M.; Clancy, Jennifer L.; Preiß, Thomas

doi:10.1371/journal.pone.0030933

Cited by 80 publications

(73 citation statements)

References 71 publications

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“…In agreement with our results, at least three putative targets in their data set match our list of direct miR-378 or miR-378* targets including alpha skeletal actin mRNA that is strongly repressed in Matkovich's data set (FC ϭ Ϫ8.24), Lactate dehydrogenase A and Grp78. As highlighted in this study and others (18,19,23,47), both miR-378 and miR-378* are coexpressed in cardiac cells. Interestingly, the ratio of each strand of the hairpin may vary according to the stage of cardiomyocyte differentiation.…”

Section: Figsupporting

confidence: 74%

“…We included miR-378* in our study because, on the contrary to most miRs, the two strands of the miR-378:miR-378* duplex have been detected in several studies. In a deep sequencing study performed in an HL-1 murine cardiac cell line, miR-378 and 378* were found to represent 1.6% and 0.1% respectively of all miRs detected in the heart, putting both of them in the top 10% of total miR expression (23). In a study performed by Vacchi-Suzzi et al in rat adult heart, miR-378* represented in average 0.003% of total miR expression in the myocardium still placing it in the top 20% of all microRNAs expressed in the heart (19).…”

Section: Micrornas (Mirs)mentioning

confidence: 99%

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Proteome Modulation in H9c2 Cardiac Cells by microRNAs miR-378 and miR-378

Mallat¹,

Tritsch²,

Ladouce³

et al. 2014

Molecular & Cellular Proteomics

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MicroRNAs are a novel class of powerful endogenous regulators of gene expression. MiR-378 and miR-378* are localized in the first intron of the Ppargc1b gene that codes the transcriptional co-activator PGC-1␤. The latter regulates energy expenditure as well as mitochondrial biogenesis. The miR-378:miR-378* hairpin is highly expressed in cardiac cells. To better assess their role in cardiomyocytes, we identified miR-378 and miR-378* targets via a proteomic screen. We established H9c2 cellular models of overexpression of miR-378 and miR-378* and identified a total of 86 down-regulated proteins in the presence of either one of these miRs. Functional annotation clustering showed that miR-378 and miR-378* regulate related pathways in cardiomyocytes, including energy metabolism, notably glycolysis, cytoskeleton, notably actin filaments and muscle contraction. Using bioinformatics algorithms we found that 20 proteins were predicted as direct targets of the miRs. We validated eight of these targets by quantitative RT-PCR and luciferase reporter assay. We found that miR-378 targets lactate dehydrogenase A and impacts on cell proliferation and survival whereas miR-378* targets cytoskeleton proteins actin and vimentin. Proteins involved in endoplasmic reticulum stress response such as chaperone and/or calcium buffering proteins GRP78, PPIA (cyclophilin A), calumenin, and GMMPA involved in glycosylation are repressed by these miRs. Our results show that the miR-378/378* hairpin establishes a connection among energy metabolism, cytoskeleton remodeling, and endoplasmic reticulum function through post-transcriptional regulation of key proteins involved in theses pathways. Molecular & Cellular Proteomics 13: 10.1074/mcp.M113.030569, 18-29, 2014.

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Section: Figsupporting

confidence: 74%

Section: Micrornas (Mirs)mentioning

confidence: 99%

Proteome Modulation in H9c2 Cardiac Cells by microRNAs miR-378 and miR-378

Mallat¹,

Tritsch²,

Ladouce³

et al. 2014

Molecular & Cellular Proteomics

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“…Thus, miR-223 5 ′ -isomiR expression appears to broaden the overall range of miR-223 targets. The prediction that 5 ′ -isomiR expression can impact miRNA target ranges is further supported by the confirmation of small sets of differentially regulated targets for an aberrant miR-307 5 ′ -isomiR in flies (Fukunaga et al 2012) and for transfected 5 ′ -isomiRs of miR-133a, miR-101, and miR-9 (Humphreys et al 2012;Llorens et al 2013;Tan et al 2014). On the other hand, it has been suggested that 5 ′ -isomiRs have highly overlapping targets (Cloonan et al 2011;Llorens et al 2013) and could therefore act redundantly, to increase the effective miRNA dosage or reduce offtarget effects (Cloonan et al 2011).…”

Section: Introductionmentioning

confidence: 82%

Divergent target recognition by coexpressed 5′-isomiRs of miR-142-3p and selective viral mimicry

Manzano

Forte

Raja

et al. 2015

RNA

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Sequence heterogeneity at the ends of mature microRNAs (miRNAs) is well documented, but its effects on miRNA function are largely unexplored. Here we studied the impact of miRNA 5 ′ -heterogeneity, which affects the seed region critical for target recognition. Using the example of miR-142-3p, an emerging regulator of the hematopoietic lineage in vertebrates, we show that naturally coexpressed 5 ′ -variants (5 ′ -isomiRs) can recognize largely distinct sets of binding sites. Despite this, both miR-142-3p isomiRs regulate exclusive and shared targets involved in actin dynamics. Thus, 5′ -heterogeneity can substantially broaden and enhance regulation of one pathway. Other 5 ′ -isomiRs, in contrast, recognize largely overlapping sets of binding sites. This is exemplified by two herpesviral 5 ′ -isomiRs that selectively mimic one of the miR-142-3p 5 ′ -isomiRs. We hypothesize that other cellular and viral 5 ′ -isomiRs can similarly be grouped into those with divergent or convergent target repertoires, based on 5 ′ -sequence features. Taken together, our results provide a detailed characterization of target recognition by miR-142-3p and its 5 ′ -isomiR-specific viral mimic. We furthermore demonstrate that miRNA 5 ′ -end variation leads to differential targeting and can thus broaden the target range of miRNAs.

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“…MicroRNA (miR) data were obtained using the next generation small-RNA sequencing, as described previously (19). Briefly, total RNA was prepared from ϳ25 mg of liver samples from singleton (C, n ϭ 3; PCUN, n ϭ 3; PIUN, n ϭ 3) and twin fetuses (C, n ϭ 3; PCUN, n ϭ 3; PIUN, n ϭ 3) using TRIzol reagent.…”

Section: Micro Rna Expressionmentioning

confidence: 99%

Impact of embryo number and maternal undernutrition around the time of conception on insulin signaling and gluconeogenic factors and microRNAs in the liver of fetal sheep

Lie

Morrison

Williams-Wyss

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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-This study aimed to determine whether exposure of the oocyte and/or embryo to maternal undernutrition results in the later programming of insulin action in the liver and factors regulating gluconeogenesis. To do this, we collect livers from singleton and twin fetal sheep that were exposed to periconceptional (PCUN; Ϫ60 to 7 days) or preimplantation (PIUN; 0 -7 days) undernutrition at 136 -138 days of gestation (term ϭ 150 days). The mRNA and protein abundance of insulin signaling and gluconeogenic factors were then quantified using qRT-PCR and Western blotting, respectively, and global microRNA expression was quantified using deep sequencing methodology. We found that hepatic PEPCK-C mRNA (P Ͻ 0.01) and protein abundance and the protein abundance of IRS-1 (P Ͻ 0.01), p110␤ (P Ͻ 0.05), PTEN (P Ͻ 0.05), CREB (P Ͻ 0.01), and pCREB (Ser 133 ; P Ͻ 0.05) were decreased in the PCUN and PIUN singletons. In contrast, hepatic protein abundance of IRS-1 (P Ͻ 0.01), p85 (P Ͻ 0.01), p110␤ (P Ͻ 0.001), PTEN (P Ͻ 0.01), Akt2 (P Ͻ 0.01), p-Akt (Ser 473 ; P Ͻ 0.01), and p-FOXO-1 (Thr24) (P Ͻ 0.01) was increased in twins. There was a decrease in PEPCK-C mRNA (P Ͻ 0.01) but, paradoxically, an increase in PEPCK-C protein (P Ͻ 0.001) in twins. Both PCUN and PIUN altered the hepatic expression of 23 specific microRNAs. We propose that the differential impact of maternal undernutrition in the presence of one or two embryos on mRNAs and proteins involved in the insulin signaling and gluconeogenesis is explained by changes in the expression of a suite of specific candidate microRNAs.pregnancy; nutrition; fetus; epigenetic IT HAS BEEN DEMONSTRATED in a range of epidemiological and experimental studies that exposure of the oocyte, embryo, or fetus to a range of environmental stressors, including poor maternal nutrition, results in poor metabolic and cardiovascular outcomes in postnatal life (8,9,13,22,25,41,42,53,56). In sheep, maternal undernutrition from 60 days before to 30 days after conception resulted in an impairment of the insulin and glucose responses to a glucose tolerance test at 10 mo after birth (49). The effects of exposure to maternal undernutrition during early gestation were also more pronounced in singleton than in twin offspring. However, it is not known whether exposure to maternal undernutrition limited to around the time of conception alone is sufficient to program changes in the insulin-signaling pathway in tissues of metabolic importance such as the liver or whether there is a differential impact of maternal undernutrition in the periconceptional period in singletons and twins.Insulin acts through the insulin receptor (IR), which is stabilized by caveolin-1 (Cav-1), resulting in a series of activations by phosphorylation of the insulin receptor substrate-1 (IRS-1) or -2 (IRS-2), phosphatidylinositol 3-kinase (PI3K), and conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3). Conversion of PIP2 to PIP3 is negatively regulated by phosphatase and tensin homolog (...

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Complexity of Murine Cardiomyocyte miRNA Biogenesis, Sequence Variant Expression and Function

Cited by 80 publications

References 71 publications

Proteome Modulation in H9c2 Cardiac Cells by microRNAs miR-378 and miR-378

Proteome Modulation in H9c2 Cardiac Cells by microRNAs miR-378 and miR-378

Divergent target recognition by coexpressed 5′-isomiRs of miR-142-3p and selective viral mimicry

Impact of embryo number and maternal undernutrition around the time of conception on insulin signaling and gluconeogenic factors and microRNAs in the liver of fetal sheep

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