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Physiological genomics [journal]
- Prepartal dietary energy alters transcriptional adaptations of the liver and subcutaneous adipose tissue of dairy cows during the transition period. [JOURNAL ARTICLE]
- Physiol Genomics 2014 Feb 25.
Overfeeding during the dry period may predispose cows to increased insulin resistance (IR) with enhanced postpartum lipolysis. We studied gene expression in the liver and subcutaneous adipose tissue (SAT) of 16 Finnish Ayrshire dairy cows fed either a controlled energy diet (CON; 99 MJ/d metabolizable energy (ME)) during the last six weeks of the dry period or high energy diet (HIGH; 141 MJ/d ME) for the first three weeks and then gradually decreasing energy allowance during three weeks to 99 MJ/d ME before the expected parturition. Tissue biopsies were collected at -10, 1 and 9 d, and blood samples at -10, 1 and 7 d relative to parturition. Overfed cows had greater dry matter, crude protein and ME intakes and ME balance before parturition. Daily milk yield, live weight and body condition score were not different between treatments. The HIGH cows tended to have greater plasma insulin and lower glucagon/insulin ratio compared with CON cows. No differences in circulating glucose, glucagon, nonesterified fatty acids and β-hydroxybutyrate concentrations, and hepatic triglyceride contents were observed between treatments. Overfeeding compared with CON resulted in lower CPT1A and PCK1, and a tendency for lower G6PC and PC expression in the liver. The HIGH group tended to have lower RETN expression in SAT than CON. No other effects of overfeeding on the expression of genes related to IR in SAT were observed. In conclusion, overfeeding energy prepartum may have compromised hepatic gluconeogenic capacity and slightly affected IR in SAT based on gene expression.
- Basal microRNA expression patterns in reward circuitry of selectively-bred high-responder and low-responder rats vary by brain region and genotype. [JOURNAL ARTICLE]
- Physiol Genomics 2014 Feb 25.
Mental health disorders involving altered reward, emotionality, and anxiety are thought to result from the interaction of individual predisposition (genetic factors) and personal experience (environmental factors) although the mechanisms that contribute to an individual's vulnerability to these disorders remain poorly understood. We used an animal model of individual variation (inbred high-responder/low-responder (bHR-bLR) rodents) known to vary in reward, anxiety and emotional processing to examine neuroanatomical expression patterns of microRNAs (miRNAs). Laser capture microdissection (LCM) was used to dissect the prelimbic cortex and the nucleus accumbens core and shell prior to analysis of basal miRNA expression in bHR and bLR male rats. These studies identified 187 miRNAs differentially expressed by genotype in at least one brain region, 10 of which were validated by qPCR. Four of these 10 qPCR-validated miRNAs demonstrated differential expression across multiple brain regions, and all miRNAs with validated differential expression between genotypes had lower expression in bHR animals compared to bLR animals. miR-484 and miR-128a expression differences between the prelimibic cortex of bHR and bLR animals were validated by semi-quantitative in situ hybridization. miRNA expression analysis independent of genotype identified 101 miRNAs differentially expressed by brain region, 7 of which validated by qPCR. Dnmt3a mRNA, a validated target of miR-29b, varied in a direction opposite that of miR-29b's differential expression between bHR and bLR animals. These data provide evidence that basal CNS miRNA expression varies in the bHR-bLR model, implicating microRNAs as potential epigenetic regulators of key neural circuits and individual differences associated with mental health disorders.
- Ex vivo culture of primary human colonic tissue for studying transcriptional responses to 1α,25(OH)2 and 25(OH) vitamin D. [JOURNAL ARTICLE]
- Physiol Genomics 2014 Feb 18.
1α,25-dihydroxyvitamin D3 (1α,25(OH)2 D3), is a steroid hormone derived from circulating 25(OH) vitamin D (25(OH) D) with chemopreventive effects in colorectal cancer (CRC). 1α,25(OH)2 D3 acts through transcriptional mechanisms; however, our understanding of vitamin D transcriptional responses in the colon is derived from studies in transformed cancer cell lines which may not represent responses in normal healthy tissue. Here, we describe the optimization of an ex vivo culture model using primary colonic biopsy samples for studying short-term transcriptional response induced by 1α,25(OH)2 D3 and 25(OH) D treatment. Colon biopsy samples from healthy subjects were maintained in primary culture and treated in parallel with 100nM 1α,25(OH)2 D3 or 62.5nM 25(OH)D and vehicle control (ethanol, EtOH). Viability was assessed using histology and enzymatic assays. Genome-wide transcriptional responses to 1α,25(OH)2 D3 were assessed and expression of 25(OH) D-targets CYP27B1 and CYP24A1 were measured by real time PCR. We show that ex vivo culture of colonic tissue remains viable for up to 8 hours. The largest number of differentially expressed genes in response to 1α,25(OH)2 D3 was noted after 6h (n=120). As proof of concept, the top up-regulated gene was CYP24A1, a well-established vitamin D-responsive gene. With 25(OH)D treatment, mRNA expression of CYP27B1 was significantly increased after 1h, while expression of CYP24A1 was greatest at 8h. Ex vivo culture can be used to assess short-term transcriptional responses to 1α,25(OH)2 D3 and 25(OH)D in primary tissue from human colon. Future studies will address inter-individual differences in transcriptional responses.
- MOLECULAR AND METABOLIC PROFILES SUGGEST THAT INCREASED LIPID CATABOLISM IN ADIPOSE TISSUE CONTRIBUTES TO LEANNESS IN DOMESTIC CHICKENS. [JOURNAL ARTICLE]
- Physiol Genomics 2014 Feb 18.
Domestic broiler chickens rapidly accumulate fat and are naturally hyperglycemic and insulin resistant, making them an attractive model for studies of human obesity. We previously demonstrated that short term (five hour) fasting rapidly upregulated pathways of fatty acid oxidation in broiler chickens and proposed that activation of these pathways may promote leanness. The objective of the current study was to characterize adipose tissue from relatively lean and fatty lines of chickens and determine if heritable leanness in chickens was associated with activation of some of the same pathways induced by fasting. We compared adipose gene expression and metabolite profiles in white adipose tissue of lean Leghorn and Fayoumi breeds to those of fattier commercial broiler chickens. Both lipolysis and expression of genes involved in fatty acid oxidation were upregulated in lean chickens compared to broilers. Although there were strong similarities between the lean lines compared to broilers, distinct expression signatures were also found between Fayoumi and Leghorn, including differences in adipogenic genes. Similarities between genetically lean and fasted chickens suggest that fatty acid oxidation in white adipose tissue is adaptively coupled to lipolysis and plays a role in heritable differences in fatness. Unique signatures of leanness in Fayoumi and Leghorn lines highlight distinct pathways that may provide insight into the basis for leanness in humans. Collectively, our results provide a number of future directions through which to fully exploit chickens as unique models for the study of human obesity and adipose metabolism.
- Serum response factor: positive and negative regulation of an epithelial gene expression network in the destrin mutant cornea. [JOURNAL ARTICLE]
- Physiol Genomics 2014 Feb 18.
Increased angiogenesis, inflammation, and proliferation are hallmarks of diseased tissues, and in vivo models of these disease phenotypes provide insight into disease pathology. Dstn(corn1) mice, deficient for the actin depolymerizing factor destrin (DSTN), display increase of serum response factor (SRF), resulting in epithelial hyperproliferation, inflammation and neovascularization in the cornea. Previous work demonstrated that conditional ablation of Srf from the corneal epithelium of Dstn(corn1) mice returns the cornea to a wild-type (WT) like state. This result implicated SRF as a major regulator of genes that contribute to abnormal phenotypes in Dstn(corn1) cornea. The purpose of this study is to identify gene networks that are affected by increased expression of Srf in the Dstn(corn1) cornea. Microarray analysis led to characterization of gene expression changes that occur when conditional knock-out of Srf rescues mutant phenotypes in the cornea of Dstn(corn1) mice. Comparison of gene expression values from WT, Dstn(corn1) mutant and Dstn(corn1) rescued cornea identified over 400 differentially expressed genes that are downstream from SRF. The majority of genes affected by SRF are down-regulated in the Dstn(corn1) mutant cornea, suggesting that increased SRF negatively affects transcription of SRF gene targets. ChIP-seq analysis on Dstn(corn1) mutant and WT tissue revealed that, despite being present in higher abundance, SRF binding is significantly decreased in the Dstn(corn1) mutant cornea. This study uses a unique model combining genetic and genomic approaches to identify genes that are regulated by SRF. These findings expand current understanding of the role of SRF in both normal and abnormal tissue homeostasis.
- Identification of human exercise-induced myokines using secretome analysis. [JOURNAL ARTICLE]
- Physiol Genomics 2014 Feb 11.
Endurance exercise is associated with significant improvements in cardio-metabolic risk parameters. A role for myokines has been hypothesized, yet limited information is available about myokines induced by acute endurance exercise in humans. Therefore the aim of the study was to identify novel exercise-induced myokines in humans. To this end, we carried out a one hour one-legged acute endurance exercise intervention in 12 male subjects and a 12 week exercise training intervention in 18 male subjects. Muscle biopsies were taken before and after acute exercise or exercise training, and were subjected to microarray-based analysis of secreted proteins (secretome). For acute exercise, secretome analysis resulted in a list of 86 putative myokines, which was reduced to 29 by applying a fold-change cut-off of 1.5. Based on that shortlist, a selection of putative myokines was measured in the plasma using ELISA or multiplex assay. From that selection, CX3CL1 (fractalkine) and CCL2 (MCP-1) increased at both mRNA and plasma level. From the known myokines, only IL-6 and FGF21 changed at the mRNA level, whereas none of the known myokines changed at the plasma level. Secretome analysis of exercise training intervention resulted in a list of 69 putative myokines. Comparing putative myokines altered by acute exercise and exercise training revealed a very limited overlap of only 13 genes. In conclusion, this study identified CX3CL1 and CCL2 as myokines that were induced by acute exercise at the gene expression and plasma level and that may be involved in communication between skeletal muscle and other organs.
- The wound healing, chronic fibrosis and cancer progression triad. [JOURNAL ARTICLE]
- Physiol Genomics 2014 Feb 11.
For decades tumors have been recognized as "wounds that do not heal." Besides the commonalities that tumors and wounded tissues share, the process of wound healing also portrays similar characteristics with chronic fibrosis. In this review, we suggest a tight interrelationship, which is governed as a concurrence of cellular and microenvironmental reactivity among wound healing, chronic fibrosis and cancer development/progression (i.e., the WHFC triad). It is clear that the same cell types, as well as soluble and matrix elements that drive wound healing (including regeneration) via distinct signaling pathways, also fuel chronic fibrosis and tumor progression. Hence, here we review the relationship between fibrosis and cancer through the lens of wound healing.
- Differential regulation of DNA methylation versus histone acetylation in cardiomyocytes during HHcy in vitro and in vivo: An epigenetic mechanism. [JOURNAL ARTICLE]
- Physiol Genomics 2014 Feb 4.
Background: The mechanisms of homocysteine (Hcy) mediated cardiac threats are poorly understood. Homocysteine being the precursor to S-adenosyl methionine (a methyl donor) through methionine, is indirectly involved in methylation phenomena for DNA, RNA and protein. We reported previously that cardiac specific deletion of NMDAR1 ameliorates homocysteine posed cardiac threats and in this study, we aim to explore the role of NMDAR1 in epigenetic mechanisms of heart failure, using cardiomyocytes during hyperhomocysteinemia (HHcy). Hypothesis: High homocysteine levels activate NMDAR1, which consequently leads to abnormal DNA methylation versus histone acetylation through modulation of DNMT1, HDAC1, miRNAs and MMP9 in cardiomyocytes. Methodology: HL-1 cardiomyocytes cultured in Claycomb media were treated with 100µM Homocysteine in a dose dependent manner. NMDAR1 antagonist (MK801) was added in the absence and presence of homocysteine at 10µM in a dose dependent manner. The expression of DNMT1, HDAC1, NMDAR1 and mir133a, mir499 was assessed by real time PCR as well as western blotting. Methylation and acetylation levels were determined by checking 5'-mc DNA methylation and chromatin immunoprecipitation. Hyperhomocysteinemic mouse models (CBS+/-) were used to confirm the results in vivo. Results: In HHcy, the expression of NMDAR1, DNMT1, and MMP9 increased with increase in H3K9 acetylation while HDAC1 and mir133a, mir499 decreased in cardiomyocytes. Similar results were obtained in heart tissues of CBS+/- mouse. Conclusion: High homocysteine levels instigate cardiovascular remodeling through NMDAR1, mir133a, mir499 and DNMT1. Decrease in HDAC1, increase in H3K9 acetylation and DNA methylation are suggestive of chromatin remodeling in HHcy.
- Differential methylation in visceral adipose tissue of obese men discordant for metabolic disturbances. [JOURNAL ARTICLE]
- Physiol Genomics 2014 Feb 4.
Obesity is associated with an increased risk of type 2 diabetes (T2D) and cardiovascular diseases (CVD). The severely obese population is heterogeneous regarding CVD risk profile. Objective: To identify metabolic pathways potentially associated with development of the metabolic syndrome (MetS) through an analysis of overrepresented pathways from differentially methylated genes between severely obese men with (MetS+) and without (MetS-) the MetS. Design and Methods: Genome-wide quantitative DNA methylation analysis in VAT of severely obese men was carried out using the Infinium HumanMethylation450 BeadChip. Differences in methylation levels between MetS+ (N = 7) and MetS- (N = 7) groups were tested. Overrepresented pathways from the list of differentially methylated genes were identified and visualized with the Ingenuity Pathway Analysis (IPA) system. Results: Differential methylation analysis between MetS+ and MetS- groups identified 8578 methylation probes (3258 annotated genes) with significant differences in methylation levels (FDR-corrected DiffScore ≥ |13| ~ p ≤ 0.05). Pathway analysis from differentially methylated genes identified 41 overrepresented (p ≤ 0.05) pathways. The most overrepresented pathways were related to structural components of the cell membrane, inflammation and immunity and cell cycle regulation. Conclusion: This study provides potential targets associated with adipose tissue dysfunction and development of the MetS.
- Polygenic risk for hypertriglyceridemia is attenuated in Japanese men with high fitness levels. [JOURNAL ARTICLE]
- Physiol Genomics 2014 Jan 28.
High cardiorespiratory fitness (CRF) is associated with a reduced risk for dyslipidemia; however, blood lipid levels are also affected by individual genetic variations. We performed a cross-sectional study to determine whether CRF modifies polygenic risk for dyslipidemia. Serum levels of triglycerides (TG), LDL cholesterol (LDL-C), and HDL cholesterol (HDL-C) were measured in 170 Japanese men (age: 20-79 years). CRF was assessed by measuring maximal oxygen uptake (VO2 max), and subjects were divided into low-fitness and high-fitness groups according to the reference VO2 max value for health promotion in Japan. We analyzed 19 single nucleotide polymorphisms (SNPs) associated with TG, LDL-C, or HDL-C levels. Based on these SNPs, we calculated 3 genetic risk scores (GRSs: TG-GRS, LDL-GRS, and HDL-GRS), and subjects were divided into low, middle, and high groups according to the tertile for each GRS. Serum TG levels of low-fitness individuals were higher in the high and middle TG-GRS groups than in the low TG-GRS group (p < 0.01, p < 0.05, respectively), whereas no differences were detected in the TG levels of high-fitness individuals among the TG-GRS groups. In contrast, the high LDL-GRS group had higher LDL-C levels than did the low LDL-GRS group, and HDL-C levels were lower in the high HDL-GRS group than in the low HDL-GRS group regardless of the fitness level (p < 0.05). These results suggest that high CRF attenuates polygenic risk for hypertriglyceridemia; however, high CRF may not modify the polygenic risk associated with high LDL-C and low HDL-C levels in Japanese men.