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Spatiotemporal Network Motif Reveals the Biological Traits of Developmental Gene Regulatory Networks in Drosophila Melanogaster

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Spatiotemporal Network Motif Reveals the Biological Traits of Developmental Gene Regulatory Networks in Drosophila Melanogaster UC Irvine UC Irvine Previously Published Works Title Spatiotemporal network motif reveals the biological traits of developmental gene regulatory networks in Drosophila melanogaster Permalink https://escholarship.org/uc/item/55k7w157 Journal BMC Systems Biology, 6(1) ISSN 1752-0509 Authors Kim, Man-Sun Kim, Jeong-Rae Kim, Dongsan et al. Publication Date 2012-05-01 DOI http://dx.doi.org/10.1186/1752-0509-6-31 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Kim et al. BMC Systems Biology 2012, 6:31 http://www.biomedcentral.com/1752-0509/6/31 RESEARCH ARTICLE Open Access Spatiotemporal network motif reveals the biological traits of developmental gene regulatory networks in Drosophila melanogaster Man-Sun Kim1, Jeong-Rae Kim1,2, Dongsan Kim1, Arthur D Lander3 and Kwang-Hyun Cho1* Abstract Background: Network motifs provided a “conceptual tool” for understanding the functional principles of biological networks, but such motifs have primarily been used to consider static network structures. Static networks, however, cannot be used to reveal time- and region-specific traits of biological systems. To overcome this limitation, we proposed the concept of a “spatiotemporal network motif,” a spatiotemporal sequence of network motifs of sub-networks which are active only at specific time points and body parts. Results: On the basis of this concept, we analyzed the developmental gene regulatory network of the Drosophila melanogaster embryo. We identified spatiotemporal network motifs and investigated their distribution pattern in time and space. As a result, we found how key developmental processes are temporally and spatially regulated by the gene network. In particular, we found that nested feedback loops appeared frequently throughout the entire developmental process. From mathematical simulations, we found that mutual inhibition in the nested feedback loops contributes to the formation of spatial expression patterns. Conclusions: Taken together, the proposed concept and the simulations can be used to unravel the design principle of developmental gene regulatory networks. Background do not operate simultaneously due to spatial and temporal To uncover the governing principles underlying complex variations. Some network motif approaches have partially biological processes, it is important to understand the considered spatial or temporal information on biological relationship between topological structures and the dynam- networks [6,7]. Papatsenko analyzed the dynamics of ical characteristics of gene regulatory networks [1-4]. One network motifs for a spatial stripe pattern formation, only promising method of investigation is to disassemble the in early embryogenesis [7], while Kim et al. explored the large regulatory network into its more basic, constituent dynamics for temporal network motifs [6]. Nevertheless, building blocks called network motifs, which recur within a patterns of spatiotemporal variations in gene regulatory network much more often than expected in random networks have not yet been explored. networks. Network motifs are considered to have been evo- In this paper, we propose a novel concept called the lutionarily selected because of their functional advantages “spatiotemporal network motif,” which is a sequence of [5]. network motifs in sub-networks that are spatiotempo- Most previous studies have identified network motifs of rally active. These network motifs are constructed by re- biological networks by implicitly assuming that all the organizing the regulations between spatiotemporally links in a network can be active or working at the same expressed genes. time. However, such approaches may not be applicable to We applied this approach to the developmental gene developmental networks where all genes and interactions regulatory network of D. melanogaster. First, we identi- fied a spatio-temporal sequence of network motifs which change according to developmental stages and regions. * Correspondence: [email protected] 1Department of Bio and Brain Engineering, Korea Advanced Institute of Then, we analyzed the pattern of spatio-temporal net- Science and Technology (KAIST), Daejeon 305-701, Republic of Korea work motifs and their dynamics (we only considered Full list of author information is available at the end of the article © 2012 Kim et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Kim et al. BMC Systems Biology 2012, 6:31 Page 2 of 10 http://www.biomedcentral.com/1752-0509/6/31 three-node network motifs for simplicity and for a con- proposed approach to identify network structures that cise illustration of the method). As a result, we found are necessary at some specific region and time. that the most frequently observed structure in the spa- tiotemporal network motif pattern is the feed-forward Unravelling region- and time-specific biological traits of loop structure. This result implies that signal-processing developmental processes via feed-forward loops is required throughout all of the We applied the proposed approach to the developmental development stages [6,8]. Another important network gene regulatory network of D. melanogaster, since develop- motif that we identified was nested feedback loops, mental processes should be driven by tightly coordinated where one feedback loop is nested inside another feed- spatio-temporal patterns of gene expression. For this case back or feed-forward loop. Such nested feedback loops study, we collected gene expression data measured at six were considered necessary for the development of a developmental stages from the BDGP (Berkeley Drosoph- central nervous system, as they should be stable and ila Genome Project) database [10] and considered six body robust against both noise and small perturbations [9]. This parts: Maternal (Ma), Endoderm (En), Mesoderm (Me), result suggests that nested feedback loops might play an Ectoderm (Ec), Central Nervous System (CNS), and important role in the elaborate regulation of developmen- Epidermis (Epi). There were 30 active sub-networks in all tal processes. Interestingly, we found that most nested (Figure 2), which we used to identify network motifs. We feedback loops had mutual inhibitory structures. Through were able to identify network motifs from 19 active sub- mathematical simulations, we showed that such mutual networks, meaning that the remaining 11 active sub- inhibitory structures can enable exclusive spatial expres- networks do not contain any network structures that occur sion of gap genes. more often than in random networks. These results cannot Taken together, the proposed concept and the simula- be obtained from conventional network motif analysis. For tions can reveal time- and region-specific biological traits instance, Motifs 3, 4, 6, 11, 12, and 13 were identified in the in dynamic processes such as the developmental gene static network [6], which is simply the union of all the pos- regulatory network, and can be widely used to investigate sible regulations between genes. However, not every com- the relationship between dynamic network structures ponent in the entire network is active throughout the and their regulatory functions. overall developmental stages and regions. With our approach, we can find new network motifs that cannot be Results identified from conventional motif analysis. The temporal Identification of spatio-temporal network motifs network motif approach [6] is more advanced, in that it Gene expression is controlled by spatiotemporally active expands to include temporal changes. Nested feedback sub-networks of a gene regulatory network (Figure 1a). loopswereidentifiedatlatestagesbyreconstructingtime In order to study the biological traits of dynamic systems varying networks, but our approach is the first to success- such as developmental processes, we need to analyze the fully identify such loops as important network motifs in structural characteristics of such spatiotemporally active overall developmental stages. Nested feedback loops were sub-networks. To this end, we propose a new concept required for pattern formation at early embryogenesis, and called “spatiotemporal network motifs,” which can be for neurogenesis at middle embryogenesis. Taken together, used to reveal region- and time-specific biological traits the proposed concept is more practical than previous at a system level and to study the relationship between approaches for analyzing developmental gene regulatory topological structures and the functional roles of spatio- networks. temporally active sub-networks. In Table 1, we summarized body parts, the correspond- Let us consider an example network with gene expres- ing network motifs, the triple genes comprising the sion data measurements taken in three regions (R1, R2 network motifs, and the Gene Ontology (GO) terms of and R3) at three time points (T1, T2 and T3), as shown three periods (early, middle, and late embryogenesis). We in Figure 1b. In this case, we should consider nine active investigated whether the genes in the spatio-temporal net- sub-networks. Figure 1b shows the network motif pat- work motifs possessed the GO terms related to each devel- tern of the nine active sub-networks. The network motifs opmental stage. In the early period of embryogenesis of the R3 sub-network
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