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Physiological genomics [journal]
- Multi-Omic integrated networks connect DNA methylation and microRNA with skeletal muscle plasticity to chronic exercise in type 2 diabetic obesity. [JOURNAL ARTICLE]
- Physiol Genomics 2014 Aug 19.
Epigenomic regulation of the transcriptome by DNA methylation and post-transcriptional gene silencing by miRNAs are potential environmental modulators of skeletal muscle plasticity to chronic exercise in healthy and diseased populations. We utilised transcriptome networks to connect exercise-induced differential methylation and miRNA with functional skeletal muscle plasticity. Biopsies of the Vastus lateralis were collected from middle aged Polynesian men and women with morbid obesity (44 kg/m(2) ± 10) and Type-2 diabetes before and following 16 weeks of resistance (n=9) or endurance training (n=8). Longitudinal transcriptome, methylome, and miRNA responses were obtained via microarray, filtered by novel effect-size based false discovery rate probe selection preceding bioinformatic interrogation. Metabolic and microvascular transcriptome topology dominated the network landscape following endurance exercise. Lipid and glucose metabolism modules were connected to: miR-29a; promoter region hypomethylation of nuclear receptor factor (NRF1) and fatty-acid transporter (SLC27A4), and hypermethylation of fatty acid synthase, and to exon hypomethylation of 6-phosphofructo-2-kinase and Ser/Thr protein kinase. Directional change in the endurance networks was validated by lower intramyocellular lipid, increased capillarity, GLUT4, hexokinase and mitochondrial enzyme activity and proteome. Resistance training also lowered lipid, increased enzyme activity, and caused GLUT4-promoter hypomethylation; however, training was inconsequential to GLUT4, capillarity, and metabolic transcriptome. miR-195 connected to negative regulation of vascular development. To conclude, integrated molecular network modelling revealed differential DNA methylation and miRNA expression changes occur in skeletal muscle in response to chronic exercise training that are most pronounced with endurance training and topographically associated with functional metabolic and microvascular plasticity relevant to diabetes rehabilitation.
- Corrigendum. [Journal Article]
- Physiol Genomics 2014 Aug 15; 46(16):615.
- Bioinformatic Approaches to Augment Study of Epithelial-to-Mesenchymal Transition (EMT) in Lung Cancer. [JOURNAL ARTICLE]
- Physiol Genomics 2014 Aug 5.
Bioinformatic approaches are intended to provide systems level insight into the complex biological processes that underlie serious diseases such as cancer. In this review we describe current bioinformatic resources, and illustrate how they have been used to study a clinically important example: epithelial-to-mesenchymal transition (EMT) in lung cancer. Lung cancer is the leading cause of cancer-related deaths and is often diagnosed at advanced stages, leading to limited therapeutic success. While EMT is essential during development and wound healing, pathological reactivation of this program by cancer cells contributes to metastasis and drug resistance, both major causes of death from lung cancer. Challenges of studying EMT include its transient nature, its molecular and phenotypic heterogeneity, and the complicated networks of rewired signaling cascades. Given the biology of lung cancer and the role of EMT, it is critical to better align the two in order to advance the impact of precision oncology. This task relies heavily on the application of bioinformatic resources. Besides summarizing recent work in this area, we use four EMT-associated genes, TGF-β (TGFB1), NEDD9/HEF1, β-catenin (CTNNB1) and E-cadherin (CDH1), as exemplars to demonstrate the current capacities and limitations of probing bioinformatic resources to inform hypothesis-driven studies with therapeutic goals.
- Expression of microRNAs and their target genes and pathways associated with ovarian follicle development in cattle. [JOURNAL ARTICLE]
- Physiol Genomics 2014 Aug 5.
Development of ovarian follicles is controlled at the molecular level by several gene products whose precise expression leads to regression or ovulation of follicles. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression through sequence-specific base pairing with target messenger RNAs (mRNAs) causing translation repression or mRNA degradation. The aim of this study was to identify miRNAs expressed in theca and/or granulosa layers and their putative target genes/pathways that are involved in bovine ovarian follicle development. By using miRCURY microarray (Exiqon) we identified 14 and 49 differentially expressed miRNAs (P < 0.01) between dominant and subordinate follicles in theca and granulosa cells, respectively. The expression levels of four selected miRNAs were confirmed by qRT-PCR. To identify target prediction and pathways of differentially expressed miRNAs Union of Genes option in DIANA miRPath v.2.0 software was used. The predicted targets for these miRNAs were enriched for pathways involving oocyte meiosis, Wnt, TGF-beta, ErbB, Insulin, P13K-Akt and MAPK signaling pathways. This study identified differentially expressed miRNAs in the theca and granulosa cells of dominant and subordinate follicles, and implicates them in having important roles in regulating known molecular pathways that determine the fate of ovarian follicle development.
- Structural changes in the gut microbiome of constipated patients. [JOURNAL ARTICLE]
- Physiol Genomics 2014 Jul 29.
Previous studies using culture based methods suggested an association between constipation and altered abundance of certain taxa of the colonic microbiome. We aim to examine the global changes in gut microbial composition of constipated patients. A cross-sectional pilot study was performed to compare stool microbial composition of 8 constipated patients and 14 non-constipated controls using 16S rRNA gene pyrosequencing. Only obese children were enrolled so that the microbiome features associated with constipation would not be obscured by those associated with obesity. The sequencing reads were processed using QIIME for quantitative analysis of the microbial composition at genus and above levels. Dietary intake for all the individuals was assessed by dietary recalls and a food frequency questionnaire. The ecological diversities of fecal microbiome of the constipated patients differed from those of the controls. Significantly decreased abundance in Prevotella, and increased representation in several genera of Firmicutes were observed in constipated patients, compared to controls. The conventional probiotic genera Lactobacillus and Bifidobacteria were not decreased in the microbiomes of the constipated patients. These alterations in the fecal microbiome of constipated patients suggested that a novel probiotic treatment including certain Prevotella strains may be more effective than conventional probiotic products incorporating Lactobacillus or Bifidobacterium species. While it is possible that the observed changes in the microbiome in constipated subjects are a consequence of a low fiber diet, these changes also predict a different pattern of bacterial fermentation end-products, such as increased butyrate production, which may contribute to pathogenesis of constipation.
- Mathematical modeling of light mediated HPA axis activity and downstream implications on the entrainment of peripheral clock genes. [JOURNAL ARTICLE]
- Physiol Genomics 2014 Jul 29.
In this work we propose a semi-mechanistic model that describes the photic signal transduction to the HPA axis that ultimately regulates the synchronization of peripheral clock genes (PCGs). Our HPA axis model predicts that photic stimulation induces a type-1 phase response curve (PRC) to cortisol's profile with increased cortisol sensitivity to light exposure in its rising phase, as well as the shortening of cortisol's period as constant light increases (Aschoff's first rule). Furthermore, our model provides insight into cortisol's phase and amplitude dependence on photoperiods and reveals that cortisol maintains highest amplitude variability when it is entrained by a balanced schedule of light and dark periods. Importantly, by incorporating the links between HPA axis and PCGs we were able to investigate how cortisol secretion impacts the entrainment of a population of peripheral cells and show that disrupted light schedules, leading to blunted cortisol secretion, fail to synchronize a population of PCGs which further signifies the loss of circadian rhythmicity in the periphery of the body.
- Effects of mtDNA in SHR-mtF344 versus SHR conplastic strains on reduced OXPHOS enzyme levels, insulin resistance, cardiac hypertrophy, and systolic dysfunction. [JOURNAL ARTICLE]
- Physiol Genomics 2014 Jul 29.
Common inbred strains of the laboratory rat can be divided into 4 major mitochondrial DNA (mtDNA) haplotype groups represented by the BN, F344, LEW, and SHR strains. In the current study, we investigated the metabolic and hemodynamic effects of the SHR versus F344 mtDNA by comparing the SHR versus SHR-mt(F344) conplastic strains that are genetically identical except for their mitochondrial genomes. Altogether 13 amino acid substitutions in protein coding genes, 7 single nucleotide polymorphisms in tRNA genes and 12 single nucleotide changes in rRNA genes were detected in F344 mtDNA when compared to SHR mtDNA. Analysis of oxidative phosphorylation system (OXPHOS) in heart left ventricles (LV), muscle and liver revealed reduced activity and content of several respiratory chain complexes in SHR-mt(F344) conplastic rats when compared to the SHR strain. Lower function of OXPHOS in LV of conplastic rats was associated with significantly increased relative ventricular mass and reduced fractional shortening which was independent of blood pressure. In addition, conplastic rats exhibited reduced sensitivity of skeletal muscles to insulin action and impaired glucose tolerance. These results provide evidence that inherited alterations in mitochondrial genome, in the absence of variation in the nuclear genome and other confounding factors, predispose to insulin resistance, cardiac hypertrophy and systolic dysfunction.
- Acclimatization to Long-Term Hypoxia: Gene Expression in Ovine Carotid Arteries. [JOURNAL ARTICLE]
- Physiol Genomics 2014 Jul 22.
Exposure to acute high altitude hypoxia is associated with an increase in cerebral blood flow (CBF) as a consequence of low arterial O2 tension. However, with acclimatization response to high altitude, CBF returns to levels similar to those at sea-level, and blood flow is maintained by increase in angiogenesis. Of consequence, dysregulation of the acclimatization responses and CBF can result in acute mountain sickness, acute cerebral and/or pulmonary edema. To elucidate the signal transduction pathways involved in successful acclimatization to high altitude, we tested the hypothesis that high-altitude associated long-term hypoxia (LTH) results in changes in gene expression of critical signaling pathways in ovine carotid arteries. We acclimatized non-pregnant adult sheep to 3801 m altitude for ∼ 110 days and conducted oligonucleotide microarray experiments on carotid arteries. Of total 118 regulated genes, 60 genes were significantly upregulated and 58 genes were significantly downregulated (each > 2-fold; P < 0.05). Major upregulated genes included suprabasin, myelin basic protein, apoliprotein B; whereas major downregulated genes included protein kinase C delta, endonucleas V, BCL6. Several of these genes are known to activate the ERK canonical signal transduction pathway and the process of angiogenesis. We conclude that the altered signal transduction molecules involved in high altitude acclimatization are associated ERK activation and angiogenesis.
- Scuba diving induces nitric oxide synthesis and the expression of inflammatory and regulatory genes of the immune response in neutrophils. [JOURNAL ARTICLE]
- Physiol Genomics 2014 Jul 8.
Objective: Scuba diving, characterized by hyperoxia and hyperbaria, could increase reactive oxygen species production which acts as signalling molecules to induce adaptation against oxidative stress. The aim was to study the effects of scuba diving immersion on neutrophil inflammatory response, the induction of oxidative damage and the NO synthesis. Design: Nine male divers performed a dive at 50 m depth for a total time of 35 min. Blood samples were obtained before diving at rest, after diving, and 3 h after the diving session. Measurements: Markers of oxidative and nitrosative damage, nitrite and the gene expression of genes related with the synthesis of nitric oxide and lipid mediators, cytokine synthesis and inflammation were determined in neutrophils. Results: The mRNA levels of genes related with the inflammatory and immune response of neutrophils, except TNF-α, myeloperoxidase and toll-like receptor (TLR) 2, significantly increased after the recovery period respect to pre-dive and post dive levels. NFκβ, IL-6 and TLR4 gene expression reported significant differences immediately after diving respect to the pre-dive values. Protein-nitrotyrosine levels significantly rose after diving and remained high during recovery, whereas no significant differences were reported in malondialdehyde. Neutrophil nitrite levels as indicative of iNOS activity progressively increased after diving and recovery. The iNOS protein levels maintained the basal values in all situations. Conclusion: Scuba diving which combines hyperoxia, hyperbaria and acute exercise induces nitrosative damage with increased nitrotyrosine levels and an inflammatory response in neutrophils.
- Genome-wide analysis of gestational gene-environment interactions in the developing kidney. [JOURNAL ARTICLE]
- Physiol Genomics 2014 Jul 8.
The G-protein coupled bradykinin B2 receptor (Bdkrb2) plays an important role in regulation of blood pressure under conditions of excess salt intake. Our previous work has shown that Bdkrb2 also plays a developmental role since Bdkrb2(-/-) embryos, but not their wild type or heterozygous littermates, are prone to renal dysgenesis in response to gestational high salt intake. Although impaired terminal differentiation and apoptosis are consistent findings in the Bdkrb2(-/-) mutant kidneys, the developmental pathways downstream of gene-environment interactions leading to the renal phenotype remain unknown. Here, we performed genome-wide transcriptional profiling on embryonic kidneys from salt-stressed Bdkrb2(+/+) and Bdkrb2(-/-) embryos. The results revealed significant alterations in key pathways regulating Wnt signaling, apoptosis, embryonic development, and cell-matrix interactions. In silico analysis revealed that nearly 12% of differentially regulated genes harbor one or more Pax2 DNA-binding sites in their promoter region. Further analysis showed that metanephric kidneys of salt-stressed Bdkrb2(-/-) have a significant downregulation of Pax2 gene expression. This was corroborated in Bdkrb2(-/-);Pax2(GFP+/tg) mice, demonstrating that Pax2 transcriptional activity is significantly repressed by gestational salt-Bdkrb2 interactions. We conclude that gestational gene (Bdkrb2) and environment (salt) interactions cooperate to impact gene expression programs in the developing kidney. Suppression of Pax2 likely contributes to the defects in epithelial survival, growth, and differentiation in salt-stressed BdkrB2(-/-) mice.