Download the Free Unbound MEDLINE PubMed App to your smartphone or tablet.
Available for iPhone, iPad, iPod touch, and Android.
Physiol Genomics [journal]
- Physiological genomics - where are we now? [Editorial]
- Physiol Genomics 2014 Dec 15; 46(24):859.
- Conditional Disruption of miR17-92 Cluster in Collagen Type-I producing Osteoblasts Result in Reduced Periosteal Bone Formation and Bone Response to exercise. [JOURNAL ARTICLE]
- Physiol Genomics 2014 Dec 9.:physiolgenomics.00107.2014.
In this study, we evaluated the role of the miR17-92 cluster in osteoblast lineage cells using a Cre-loxP approach in which Cre expression is driven by the entire regulatory region of the type-I collagen α2 gene. Conditional knockout (cKO) mice showed a 13-34% reduction in total body BMC and area with little or no change in BMD by DXA at 2, 4 and 8 weeks in both genders. Micro-CT analyses of the femur revealed an 8% reduction in length and 25-27% reduction in total volume (TV) at the diaphyseal and metaphyseal sites. Neither cortical nor trabecular vBMD was different in the cKO mice. Bone strength (maximum load) was reduced by 10% with no change in bone toughness. Quantitative histomorphometric analyses revealed a 28% reduction in the periosteal bone formation rate and in the mineral apposition rate but with no change in the resorbing surface. Expression levels of periostin, Elk3, Runx2 genes that are targeted by microRNAs from the cluster were decreased by 25-30% in the bones of cKO mice. In order to determine the contribution of the miR17-92 cluster to the mechanical strain effect on periosteal bone formation, cKO and control mice were subjected to 2 weeks of mechanical loading by four point bending. We found that the periosteal bone response to mechanical strain was significantly reduced in the cKO mice. We conclude that the miR17-92 cluster expressed in type I collagen producing cells is a key regulator of periosteal bone formation in mice.
- Polycystin-1 and Gα12 regulate the cleavage of E-cadherin in kidney epithelial cells. [JOURNAL ARTICLE]
- Physiol Genomics 2014 Dec 9.:physiolgenomics.00090.2014.
Interaction of polycystin-1 (PC1) and Gα12 is important for development of kidney cysts in autosomal dominant polycystic kidney disease (ADPKD). The integrity of cell polarity and cell-cell adhesions (mainly E-cadherin-mediated adherens junction) is altered in the renal epithelial cells of ADPKD. However, the key signaling pathway for this alteration is not fully understood. Madin-Darby canine kidney (MDCK) cells maintain the normal integrity of epithelial cell polarity and adherens junctions. Here, we found that deletion of Pkd1 increased activation of Gα12, which then promoted the cystogenesis of MDCK cells. The morphology of these cells was altered after the activation of Gα12. By using liquid chromatography-mass spectrometry (LC-MS), we found several proteins that could be related this change in the extracellular milieu. E-cadherin was one of the most abundant peptides after active Gα12 was induced. Gα12 activation or Pkd1 deletion increased the shedding of E-cadherin, which was mediated via increased ADAM10 activity. The increased shedding of E-cadherin was blocked by knockdown of ADAM10 or specific ADAM10 inhibitor GI254023X. Pkd1 deletion or G 12 activation also changed the distribution of E-cadherin in kidney epithelial cells and caused β-catenin to shift from cell membrane to nucleus. Finally, ADAM10 inhibitor, GI254023X, blocked the cystogenesis induced by PC1 knockdown or Gα12 activation in renal epithelial cells. Our results demonstrate that the E-cadherin/β-catenin signaling pathway is regulated by PC1 and Gα12 via ADAM10. Specific inhibition of this pathway, especially ADAM10 activity, could be a novel therapeutic regimen for ADPKD.
- MicroRNAs Associated with Exercise and Diet: A Systematic Review. [JOURNAL ARTICLE]
- Physiol Genomics 2014 Dec 2.:physiolgenomics.00095.2014.
MicroRNAs are post-transcriptional regulators of gene expression. MicroRNAs reflect individual biologic adaptation to exposures in the environment. As such, measurement of circulating microRNAs presents an opportunity to evaluate biologic changes associated with behavioral interventions (i.e., exercise, diet) for weight loss. The aim of this manuscript is to perform a systematic review of the literature to summarize what is known about circulating microRNAs associated with exercise, diet, and weight loss. We performed a systematic review of three scientific databases. We included studies reporting on circulating microRNAs associated with exercise, and diet, and weight loss in humans. Of 1219 studies identified in our comprehensive database search, 14 were selected for inclusion. Twelve reported on microRNAs associated with exercise and 2 reported on microRNAs associated with diet and weight loss. The majority of studies used a quasi-experimental, cross-sectional design. There were numerous differences in the type and intensity of exercise and dietary interventions, the biologic source of microRNAs, and the methodological approaches used quantitate microRNAs. Data from several studies support an association between circulating microRNAs and exercise. The evidence for an association between circulating microRNAs and diet is weaker due to a small number of studies. Additional research is needed to validate previous observations using methodologically rigorous approaches to microRNA quantitation in order to determine the specific circulating microRNA signatures associated with behavioral approaches to weight loss. Future directions include longitudinal studies to determine if circulating microRNAs are predictive of response to behavioral interventions.
- PBMCs express a transcriptome signature predictor of oxygen uptake responsiveness to endurance exercise training in men. [JOURNAL ARTICLE]
- Physiol Genomics 2014 Dec 2.:physiolgenomics.00072.2014.
Peripheral blood cells are an accessible environment in which to visualize exercise-induced alterations in global gene expression patterns. We aimed to identify a peripheral blood mononuclear cell (PBMC) signature represented by alterations in gene expression, in response to a standardized endurance exercise training. Additionally, we searched for molecular classifiers of the variability in oxygen uptake (VO2). Healthy untrained policemen recruits (n=13; 25±3 yrs) were selected. VO2peak (measured by cardiopulmonary exercise testing) and total RNA from PBMCs were obtained before and after 18 weeks of running endurance training (3 times/wk; 60min). Total RNA was used for whole-genome expression analysis using Affymetrix GeneChip(®) HuGene 1.0 ST. Data were normalized using the RMA algorithm. PCA analysis was used to perform correlations between baseline gene expression and VO2peak. A set of 211 transcripts was differentially expressed (ANOVA, P<0.05 and fold change >1.3). Functional enrichment analysis revealed that transcripts were mainly related to immune function, cell cycle processes, development, and growth. Baseline expression of 98 and 53 transcripts was associated with the absolute and relative VO2peakresponse with a strong correlation (r>0.75; P<0.01), respectively, and this panel was able to classify the 13 individuals according to their potential to improve oxygen uptake. A subset of 10 transcripts represented these signatures to a similar extent. PBMCs reveal a transcriptional signature responsive to endurance training. Additionally, a baseline transcriptional signature was associated with changes in VO2peak. Results might illustrate the possibility of obtaining molecular classifiers of endurance capacity changes through a minimally invasive blood sampling procedure.
- Human aldosterone synthase gene polymorphism promotes miRNA binding and regulates gene expression. [Journal Article]
- Physiol Genomics 2014 Dec 15; 46(24):860-5.
Hypertension is a serious risk factor for myocardial infarction, heart failure, vascular disease, stroke, and renal failure. Like other complex diseases, hypertension is caused by a combination of genetic and environmental factors. The renin-angiotensin-aldosterone system plays an important role in the regulation of blood pressure. The octapeptide angiotensin II (ANG II) is one of the most active vasopressor agents and is obtained from the precursor molecule, angiotensinogen, by the combined proteolytic action of renin and angiotensin-converting enzyme. ANG II increases the expression of aldosterone synthase (coded by Cyp11B2 gene), which is the rate-limiting enzyme in the biosynthesis of aldosterone. Previous studies have shown that increased expression of aldosterone synthase increases blood pressure and cardiac hypertrophy in transgenic mice. Human Cyp11B2 gene has a T/C polymorphism at -344 positions in its 5'-untranslated region (UTR), and the -344T allele is associated with hypertension. Human Cyp11B2 gene also has an A/G polymorphism at 735 position in its 3'-UTR (rs28491316) that is in linkage disequilibrium with single nucleotide polymorphism at -344. We show here that 1) microRNA (miR)-766 binds to the 735G-allele and not the 735A-allele of the hCyp11B2 gene and 2) transfection of miR-766 reduces the human aldosterone synthase mRNA and protein level in human adrenocortical cells H295R. These studies suggest that miR-766 may downregulate the expression of human aldosterone synthase gene and reduce blood pressure in human subjects containing -344T allele.
- In utero exposure to prepregnancy maternal obesity and postweaning high-fat diet impair regulators of mitochondrial dynamics in rat placenta and offspring. [Journal Article]
- Physiol Genomics 2014 Dec 1; 46(23):841-50.
The proportion of pregnant women who are obese at conception continues to rise. Compelling evidence suggests the intrauterine environment is an important determinant of offspring health. Maternal obesity and unhealthy diets are shown to promote metabolic programming in the offspring. Mitochondria are maternally inherited, and we have previously shown impaired mitochondrial function in rat offspring exposed to maternal obesity in utero. Mitochondrial health is maintained by mitochondrial dynamics, or the processes of fusion and fission, which serve to repair damaged mitochondria, remove irreparable mitochondria, and maintain mitochondrial morphology. An imbalance between fusion and fission has been associated with obesity, insulin resistance, and reproduction complications. In the present study, we examined the influence of maternal obesity and postweaning high-fat diet (HFD) on key regulators of mitochondrial fusion and fission in rat offspring at important developmental milestones which included postnatal day (PND)35 (2 wk HFD) and PND130 (∼16 wk HFD). Our results indicate HFD-fed offspring had reduced mRNA expression of presenilin-associated rhomboid-like (PARL), optic atrophy (OPA)1, mitofusin (Mfn)1, Mfn2, fission (Fis)1, and nuclear respiratory factor (Nrf)1 at PND35, while OPA1 and Mfn2 remained decreased at PND130. Putative transcriptional regulators of mitochondrial dynamics were reduced in rat placenta and offspring liver and skeletal muscle [peroxisome proliferator-activated receptor gamma coactivator (PGC1)α, PGC1β, and estrogen-related receptor (ERR)α], consistent with indirect calorimetry findings revealing reduced energy expenditure and impaired fat utilization. Overall, maternal obesity detrimentally alters mitochondrial targets that may contribute to impaired mitochondrial health and increased obesity susceptibility in later life.
- TNF-α alters the release and transfer of microparticle-encapsulated miRNAs from endothelial cells. [Journal Article]
- Physiol Genomics 2014 Nov 15; 46(22):833-40.
MicroRNAs (miRNAs) encapsulated within microparticles (MPs) are likely to have a role in cell-to-cell signaling in a variety of diseases, including atherosclerosis. However, little is known about the mechanisms by which different cell types release and transfer miRNAs. Here, we examined TNF-α-induced release of MP-encapsulated miR-126, miR-21, and miR-155 from human aortic endothelial cells (ECs) and their transfer to recipient cells. ECs were treated with TNF-α (100 ng/ml) in the presence or absence of inhibitors that target different MP production pathways. MPs released in response to TNF-α were characterized by: 1) 70-80% decrease in miRNA/MP levels for miR-126 and -21 but a significant increase in pre-miR-155 and miR-155 (P < 0.05), 2) 50% reduction in uptake by recipient cells (P < 0.05), and 3) diminished ability to transfer miRNA to recipient cells. Cotreatment of donor ECs with TNF-α and caspase inhibitor (Q-VD-OPH, 10 μM) produced MPs that had: 1) 1.5- to 2-fold increase in miRNA/MP loading, 2) enhanced uptake by recipient cells (2-fold), and 3) increased ability to transfer miR-155. Cotreatment of ECs with TNF-α and Rho-associated kinase (ROCK) inhibitor (10 μM) produced MPs with features similar to those produced by TNF-α treatment alone. Our data indicate that TNF-α induced the production of distinct MP populations: ROCK-dependent, miRNA-rich MPs that effectively transferred their cargo and were antiapoptotic, and caspase-dependent, miRNA-poor MPs that were proapoptotic. These data provide insight into the relationship between MP production and extracellular release of miRNA, as well as the potential of encapsulated miRNA for cell-to-cell communication.
- Dietary supplementation with polyunsaturated fatty acid during pregnancy modulates DNA methylation at IGF2/H19 imprinted genes and growth of infants. [JOURNAL ARTICLE]
- Physiol Genomics 2014 Oct 7.
Epigenetic regulation of imprinted genes is regarded as a highly plausible explanation for linking dietary exposures in early life with the onset of diseases during childhood and adulthood. We sought to test whether prenatal dietary supplementation with docosahexaenoic acid (DHA) during pregnancy may modulate epigenetic states at birth. This study was based on a randomized intervention trial conducted in Mexican pregnant women supplemented daily with 400 mg of DHA or a placebo from gestation week 18-22 to parturition. We applied quantitative profiling of DNA methylation states at IGF2 promoter 3 (IGF2 P3), IGF2 differentially methylated region (DMR), and H19 DMR in cord blood mononuclear cells of the DHA-supplemented group (n=131) and the control group (n=130). In stratified analyses, DNA methylation levels in IGF2 P3 were significantly higher in the DHA group than the control group in preterm infants (p=0.04). We also observed a positive association between DNA methylation levels and maternal body mass index (BMI); IGF2 DMR methylation was higher in the DHA group than the control group in infants of overweight mothers (p=0.03). In addition, at H19 DMR, methylation levels were significantly lower in the DHA group than the control group in infants of normal weight mothers (p=0.01). Finally, methylation levels at IGF2/H19 imprinted regions were associated with maternal BMI. These findings suggest that epigenetic mechanisms may be modulated by DHA, with potential impacts on child growth and development.
- Identification of genes whose expression is altered by obesity throughout the arterial tree. [Journal Article]
- Physiol Genomics 2014 Nov 15; 46(22):821-32.
We used next-generation RNA sequencing (RNA-Seq) technology on the whole transcriptome to identify genes whose expression is consistently affected by obesity across multiple arteries. Specifically, we examined transcriptional profiles of the iliac artery as well as the feed artery, first, second, and third branch order arterioles in the soleus, gastrocnemius, and diaphragm muscles from obese Otsuka Long-Evans Tokushima Fatty (OLETF) and lean Long-Evans Tokushima Otsuka (LETO) rats. Within the gastrocnemius and soleus muscles, the number of genes differentially expressed with obesity tended to increase with increasing branch order arteriole number (i.e., decreasing size of the artery). This trend was opposite in the diaphragm. We found a total of 15 genes that were consistently upregulated with obesity (MIS18A, CTRB1, FAM151B, FOLR2, PXMP4, OAS1B, SREBF2, KLRA17, SLC25A44, SNX10, SLFN3, MEF2BNB, IRF7, RAD23A, LGALS3BP) and five genes that were consistently downregulated with obesity (C2, GOLGA7, RIN3, PCP4, CYP2E1). A small fraction (∼9%) of the genes affected by obesity was modulated across all arteries examined. In conclusion, the present study identifies a select number of genes (i.e., 20 genes) whose expression is consistently altered throughout the arterial network in response to obesity and provides further insight into the heterogeneous vascular effects of obesity. Although there is no known direct function of the majority of 20 genes related to vascular health, the obesity-associated upregulation of SREBF2, LGALS3BP, IRF7, and FOLR2 across all arteries is suggestive of an unfavorable vascular phenotypic alteration with obesity. These data may serve as an important resource for identifying novel therapeutic targets against obesity-related vascular complications.