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Physiological genomics [journal]
- Dynamic Gene Expression Patterns in Animal Models of Early and Late Heart Failure Reveal Biphasic-Bidirectional Transcriptional Activation of Signaling Pathways. [JOURNAL ARTICLE]
- Physiol Genomics 2014 Aug 26.
Background: Altered cardiac gene expression in heart failure (HF) has mostly been identified by single-point analysis of end-stage disease. This may miss earlier changes in gene expression that are transient and/or directionally opposite to those observed later. Results: Myocardial datasets from the largest microarray data repository (Gene Expression Omnibus) yielded six HF studies with time-course data. Differentially expressed transcripts between non-failing controls, early-HF (<3 days after cardiac insult) and late-HF (usually >2 weeks) were determined, and analysis of KEGG pathways and predicted regulatory control elements performed. We found that gene expression followed varying patterns: Downregulation of metabolic pathways occurred early and was sustained into late stage-HF. In contrast, most signaling pathways undergo a complex biphasic pattern: Calcium signaling, p53, apoptosis and MAP-kinase pathways displayed a bi-directional response, declining early but rising late. These profiles were compatible with specific miRNA and transcription regulators: Estrogen-related receptor-α (Esrra) and myocyte-enhancer factor-2 (Mef2) binding sites were overrepresented in the promoter regions of downregulated transcripts. Concurrently, there were overrepresented binding sites for E2f and ETS family members (E-Twenty Six, including Gabp, Elf1, and Ets2), serum response (Srf) and interferon regulated factor (Irf) in biphasic-bidirectional and late-upregulated transcripts. Binding sites for miRNAs downregulated by HF were more common in up-regulated transcripts (e.g. miRNA-22,-133a/b, and -150 in early-HF and miRNA-1,-9,-499 in late-HF). Conclusions: During the development of HF, metabolic gene classes show early and sustained downregulation in HF, while signaling pathways undergo a complex biphasic pattern with early down- and more pronounced late upregulation.
- miR-21 in Ischemia/Reperfusion Injury: A Double-edged Sword? [JOURNAL ARTICLE]
- Physiol Genomics 2014 Aug 26.
MicroRNAs (miRNAs) are endogenous, small RNA molecules that suppress expression of targeted mRNA. miR-21, one of the most extensively studied miRNAs, is importantly involved in divergent pathophysiological processes relating to ischemia/reperfusion (I/R) injury, such as inflammation and angiogenesis. The role of miR-21 in renal I/R is complex, with both protective and pathological pathways being regulated by miR-21. Preconditioning-induced upregulation of miR-21 contributes to the protection against subsequent renal I/R injury through the targeting of genes such as the pro-apoptotic gene programmed cell death 4 and interactions between miR-21 and hypoxia-inducible factor. Conversely, long-term elevation of miR-21 may be detrimental to the organ by promoting the development of renal interstitial fibrosis following I/R injury. miR-21 is importantly involved in several pathophysiological processes related to I/R injury including inflammation and angiogenesis as well as the biology of stem cells that could be used to treat I/R injury, however, the effect of miR-21 on these processes in renal I/R injury remains to be studied.
- 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.