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  • 11
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    Next-generation sequencing identifies TGF-β1-associated gene expression profiles in renal epithelial cells reiterated in human diabetic nephropathy (2012)
    Elsevier
    Details
    Publication Date: 2012-04-01
    Print ISSN: 0925-4439
    Electronic ISSN: 1879-260X
    Topics: Biology , Chemistry and Pharmacology , Medicine , Physics
    Published by Elsevier
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  • 12
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    Bi-directional gene set enrichment and canonical correlation analysis identify key diet-sensitive pathways and biomarkers of metabolic syndrome (2010)
    BioMed Central
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    Publication Date: 2010-10-07
    Description: Background Currently, a number of bioinformatics methods are available to generate appropriate lists of genes from a microarray experiment. While these lists represent an accurate primary analysis of the data, fewer options exist to contextualise those lists. The development and validation of such methods is crucial to the wider application of microarray technology in the clinical setting. Two key challenges in clinical bioinformatics involve appropriate statistical modelling of dynamic transcriptomic changes, and extraction of clinically relevant meaning from very large datasets. Results Here, we apply an approach to gene set enrichment analysis that allows for detection of bi-directional enrichment within a gene set. Furthermore, we apply canonical correlation analysis and Fisher's exact test, using plasma marker data with known clinical relevance to aid identification of the most important gene and pathway changes in our transcriptomic dataset. After a 28-day dietary intervention with high-CLA beef, a range of plasma markers indicated a marked improvement in the metabolic health of genetically obese mice. Tissue transcriptomic profiles indicated that the effects were most dramatic in liver (1270 genes significantly changed; p 〈 0.05), followed by muscle (601 genes) and adipose (16 genes). Results from modified GSEA showed that the high-CLA beef diet affected diverse biological processes across the three tissues, and that the majority of pathway changes reached significance only with the bi-directional test. Combining the liver tissue microarray results with plasma marker data revealed 110 CLA-sensitive genes showing strong canonical correlation with one or more plasma markers of metabolic health, and 9 significantly overrepresented pathways among this set; each of these pathways was also significantly changed by the high-CLA diet. Closer inspection of two of these pathways - selenoamino acid metabolism and steroid biosynthesis - illustrated clear diet-sensitive changes in constituent genes, as well as strong correlations between gene expression and plasma markers of metabolic syndrome independent of the dietary effect. Conclusion Bi-directional gene set enrichment analysis more accurately reflects dynamic regulatory behaviour in biochemical pathways, and as such highlighted biologically relevant changes that were not detected using a traditional approach. In such cases where transcriptomic response to treatment is exceptionally large, canonical correlation analysis in conjunction with Fisher's exact test highlights the subset of pathways showing strongest correlation with the clinical markers of interest. In this case, we have identified selenoamino acid metabolism and steroid biosynthesis as key pathways mediating the observed relationship between metabolic health and high-CLA beef. These results indicate that this type of analysis has the potential to generate novel transcriptome-based biomarkers of disease.
    Electronic ISSN: 1471-2105
    Topics: Biology , Computer Science
    Published by BioMed Central
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  • 13
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    Model-based clustering reveals vitamin D dependent multi-centrality hubs in a network of vitamin-related proteins (2011)
    BioMed Central
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    Publication Date: 2011-12-01
    Description: Background Nutritional systems biology offers the potential for comprehensive predictions that account for all metabolic changes with the intricate biological organization and the multitudinous interactions between the cellular proteins. Protein-protein interaction (PPI) networks can be used for an integrative description of molecular processes. Although widely adopted in nutritional systems biology, these networks typically encompass a single category of functional interaction (i.e., metabolic, regulatory or signaling) or nutrient. Incorporating multiple nutrients and functional interaction categories under an integrated framework represents an informative approach for gaining system level insight on nutrient metabolism. Results We constructed a multi-level PPI network starting from the interactions of 200 vitamin-related proteins. Its final size was 1,657 proteins, with 2,700 interactions. To characterize the role of the proteins we computed 6 centrality indices and applied model-based clustering. We detected a subgroup of 22 proteins that were highly central and significantly related to vitamin D. Immune system and cancer-related processes were strongly represented among these proteins. Clustering of the centralities revealed a degree of redundancy among the indices; a repeated analysis using subsets of the centralities performed well in identifying the original set of 22 most central proteins. Conclusions Hierarchical and model-based clustering revealed multi-centrality hubs in a vitamin PPI network and redundancies among the centrality indices. Vitamin D-related proteins were strongly represented among network hubs, highlighting the pervasive effects of this nutrient. Our integrated approach to network construction identified promiscuous transcription factors, cytokines and enzymes - primarily related to immune system and cancer processes - representing potential gatekeepers linking vitamin intake to disease.
    Electronic ISSN: 1752-0509
    Topics: Biology
    Published by BioMed Central
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  • 14
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    Nonlinear transcriptomic response to dietary fat intake in the small intestine of C57BL/6J mice (2016)
    BioMed Central
    In:  BMC Genomics, 17 (1).
    Details
    Publication Date: 2019-02-01
    Description: Background: A high caloric diet, in conjunction with low levels of physical activity, promotes obesity. Many studies are available regarding the relation between dietary saturated fats and the etiology of obesity, but most focus on liver, muscle and white adipose tissue. Furthermore, the majority of transcriptomic studies seek to identify linear effects of an external stimulus on gene expression, although such an assumption does not necessarily hold. Our work assesses the dose-dependent effects of dietary fat intake on differential gene expression in the proximal, middle and distal sections of the small intestine in C57BL/6J mice. Gene expression is analyzed in terms of either linear or nonlinear responses to fat intake. Results: The highest number of differentially expressed genes was observed in the middle section. In all intestine sections, most of the identified processes exhibited a linear response to increasing fat intake. The relative importance of logarithmic and exponential responses was higher in the proximal and distal sections, respectively. Functional enrichment analysis highlighted a constantly linear regulation of acute-phase response along the whole small intestine, with up-regulation of Serpina1b. The study of gene expression showed that exponential down-regulation of cholesterol transport in the middle section is coupled with logarithmic up-regulation of cholesterol homeostasis. A shift from linear to exponential response was observed in genes involved in the negative regulation of caspase activity, from middle to distal section (e.g., Birc5, up-regulated). Conclusions: The transcriptomic signature associated with inflammatory processes preserved a linear response in the whole small intestine (e.g., up-regulation of Serpina1b). Processes related to cholesterol homeostasis were particularly active in the middle small intestine and only the highest fat intake down-regulated cholesterol transport and efflux (with a key role played by the down-regulation of ATP binding cassette transporters). Characterization of nonlinear patterns of gene expression triggered by different levels of dietary fat is an absolute novelty in intestinal studies. This approach helps identifying which processes are overloaded (i.e., positive, logarithmic regulation) or arrested (i.e., negative, exponential regulation) in response to excessive fat intake, and can shed light on the relationships linking lipid intake to obesity and its associated molecular disturbances.
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    Diversity of key players in the microbial ecosystems of the human body (2015)
    Nature Publishing Group
    In:  Scientific Reports, 5 . p. 15920.
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    Publication Date: 2020-11-09
    Description: Coexisting bacteria form various microbial communities in human body parts. In these ecosystems they interact in various ways and the properties of the interaction network can be related to the stability and functional diversity of the local bacterial community. In this study, we analyze the interaction network among bacterial OTUs in 11 locations of the human body. These belong to two major groups. One is the digestive system and the other is the female genital tract. In each local ecosystem we determine the key species, both the ones being in key positions in the interaction network and the ones that dominate by frequency. Beyond identifying the key players and discussing their biological relevance, we also quantify and compare the properties of the 11 networks. The interaction networks of the female genital system and the digestive system show totally different architecture. Both the topological properties and the identity of the key groups differ. Key groups represent four phyla of prokaryotes. Some groups appear in key positions in several locations, while others are assigned only to a single body part. The key groups of the digestive and the genital tracts are totally different.
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  • 16
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    A network analysis of cofactor-protein interactions for analyzing associations between human nutrition and diseases (2016)
    Nature Research
    In:  Scientific Reports, 6 (19633).
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    Publication Date: 2019-02-01
    Description: The involvement of vitamins and other micronutrients in intermediary metabolism was elucidated in the mid 1900's at the level of individual biochemical reactions. Biochemical pathways remain the foundational knowledgebase for understanding how micronutrient adequacy modulates health in all life stages. Current daily recommended intakes were usually established on the basis of the association of a single nutrient to a single, most sensitive adverse effect and thus neglect interdependent and pleiotropic effects of micronutrients on biological systems. Hence, the understanding of the impact of overt or sub-clinical nutrient deficiencies on biological processes remains incomplete. Developing a more complete view of the role of micronutrients and their metabolic products in protein-mediated reactions is of importance. We thus integrated and represented cofactor-protein interaction data from multiple and diverse sources into a multi-layer network representation that links cofactors, cofactor-interacting proteins, biological processes, and diseases. Network representation of this information is a key feature of the present analysis and enables the integration of data from individual biochemical reactions and protein-protein interactions into a systems view, which may guide strategies for targeted nutritional interventions aimed at improving health and preventing diseases.
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