Tissue-to-tissue networks: Next Level in Systems Biology of Obesity
For a long time biological interaction network studies were focused on single tissue analyzes. Single tissue analyzes mostly ignored the complexity of biological systems emerging due to complex array of networks operating within and between tissues. Recently a group led by Eric Schadt has reported very first systematic approach to study inter-tissue relationships. They have formulated a generalized framework for constructing tissue-to-tissue coexpression (TTC) networks between genes in heterogeneous tissues. In order to understand the systems level dynamics of obesity in mice Dobrin et al. have implemented their framework to construct scale-free coexpression networks between genes in the hypothalamus and peripheral tissues. Obesity is complex disease which is basically caused by systems level energy imbalance between hypothalamus and metabolic tissues such as adipose, muscle, stomach, intestine, liver , and pancreas. Genetic and environmental perturbations to gene-networks connecting the hypothalamus and these peripheral tissues is one of the major reasons for energy imbalance at the systems level. Multi-tissue physiological control of obesity is derived from feedback mechanism between hypothalamus and peripheral tissues where hypothalamus receives and integrates signals from peripheral tissue and accordingly feeds the signal to maintain a energy balance. Tissue-to-tissue coexpression (TTC) network can reveal the inherent communication between these tissues and elucidate genes or group of genes active in one tissue that are able to induce gene activity changes in other tissues.
(Display of the Adipose-Hypothalamus TTC network at p value threshold 10-8. Red and green edges denote negative and positive correlations, respectively. Adipose nodes in the network are marked as green circles while hypothalamus nodes are marked as red diamonds.)For an axis of hypothalamus, adipose and liver (HAL) tissues, considering each possible pair of tissues, three TTC networks- adipose-hypothalamus (AH), hypothalamus-liver (HL) and adipose-liver (AL) were constructed by identifying significantly correlated expression traits. Further
Nodes in the TTC networks represent gene expression traits from each tissue in the TTC network, thus by adipose gene we mean expression levels corresponding to the gene in adipose tissue, and similarly for hypothalamus and liver genes. Two nodes in a TTC network are connected if the gene expression traits are significantly correlated across the 2 tissues with respect to a predefined significance threshold. Therefore, unlike classical tissue specific [gene-gene] coexpression networks, TTC networks are bipartite graphs with respect to the corresponding tissues
Topologically TTC networks for the three tissue pairs are very similar although the diameter of these networks are significantly different. Network diameter is significant in terms of importance of tissues in the axis. For example the diameter of hypothalamus centric networks, AH and HL is almost twice as large as the non-hypothalamic AL network diameter which projects hypothalamus as primary controller of the HAL axis, very much according to our previous understanding. In order to understand whether TTC can provide additional insights about underlying system or not, authors examined the possible overlap between TTC networks with corresponding single tissue specific gene-gene coexpression (GGC) networks after generating independent GGC networks for each tissue. Subsequently they concluded that
via the TTC networks, we have identified entire classes of genes that are systematically ignored in single tissue analyses because they form, on average, no meaningful connections with other genes within a given tissue, but instead are enriched for genes in one tissue that are strongly connected with genes in a different tissue.
(Single tissue projections to the Adipose-Hypothalamus TTC network where Adipose and hypothalamus modules (color shaded rectangles) derived from independent analysis of each tissue’s gene-gene coexpression (GGC) network and their overlap with the Adipose-Hypothalamus TTC network)Also the TTC networks are highly modularize, and by applying a partitioning strategy function specific coherent subnetworks were identified. Subnetworks define the TTC network backbone. For the AH TCC network several subnetworks are enriched in GO Biological Process (GOBP) categories for either adipose(genes associated with obesity) or hypothalamus ( genes involved in circadian rhythm) genes. Most importantly circadian subnetwork forms center of all TTC networks which connects all other subnetworks in the network which is again very much according to our previous understanding that disregulation of several genes in the circadian subnetwork lead to obesity by disrupting energy balance and glucose homeostasis.
(Adipose-Hypothalamus network backbone where each subnetwork contributes to the backbone with its most representative genes that helps identifying the core relationships from the network. Each of these subnetworks are characterized by highly interconnected sets of genes enriched for common functional categories in the Gene Ontology such as circadian rhythm, energy balance, stress response and others.)In summery, TTC network based approach brings new insights those could have been never revealed with single tissue analyzes.
References:
Dobrin, R., Zhu, J., Molony, C., Argman, C., Parrish, M., Carlson, S., Allan, M., Pomp, D., & Schadt, E. (2009). Multi-tissue coexpression networks reveal unexpected subnetworks associated with disease Genome Biology, 10 (5) DOI: 10.1186/gb-2009-10-5-r55
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Tissue-to-tissue networks: Next Level in Systems Biology of Obesity: For a long time biological interaction netw.. http://tinyurl.com/qnkaun
Tissue-to-tissue networks: Next Level in Systems Biology of Obesity: For a long time biological interaction netw.. http://tinyurl.com/qnkaun
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Tissue-to-tissue networks: Next Level in Systems Biology of Obesity (Abhishek Tiwari’s Blog): … scale-free coe.. http://tinyurl.com/oepwhk
Tissue-to-tissue networks: Next Level in Systems Biology of Obesity (Abhishek Tiwari’s Blog): … scale-free coe.. http://tinyurl.com/oepwhk
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