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WIREs Syst Biol Med
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Hierarchical approaches for systems modeling in cardiac development

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Abstract Ordered cardiac morphogenesis and function are essential for all vertebrate life. The heart begins as a simple contractile tube, but quickly grows and morphs into a multichambered pumping organ complete with valves, while maintaining regulation of blood flow and nutrient distribution. Though not identical, cardiac morphogenesis shares many molecular and morphological processes across vertebrate species. Quantitative data across multiple time and length scales have been gathered through decades of reductionist single variable analyses. These range from detailed molecular signaling pathways at the cellular levels to cardiac function at the tissue/organ levels. However, none of these components act in true isolation from others, and each, in turn, exhibits short‐ and long‐range effects in both time and space. With the absence of a gene, entire signaling cascades and genetic profiles may be shifted, resulting in complex feedback mechanisms. Also taking into account local microenvironmental changes throughout development, it is apparent that a systems level approach is an essential resource to accelerate information generation concerning the functional relationships across multiple length scales (molecular data vs physiological function) and structural development. In this review, we discuss relevant in vivo and in vitro experimental approaches, compare different computational frameworks for systems modeling, and the latest information about systems modeling of cardiac development. Finally, we conclude with some important future directions for cardiac systems modeling. WIREs Syst Biol Med 2013, 5:289–305. doi: 10.1002/wsbm.1217 This article is categorized under: Models of Systems Properties and Processes > Cellular Models Developmental Biology > Developmental Processes in Health and Disease Biological Mechanisms > Regulatory Biology

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The objective of systems biology is to integrate low‐ and high‐throughput data with predictive computer modeling to better understand the properties of networks and cell systems important to human health. To apply such an approach, one must identify the core architecture driving a cellular process through biological networks, gather both high‐ and low‐throughput quantitative data from single factor experiments, train and validate the model for physiological relevance, and run simulations in order to prioritize wet experiments.

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Examples of four functional networks driving the development of different anatomical structures in the human heart. These four networks were constructed by analyzing the interaction patterns of four different sets of cardiac development (CD) proteins corresponding to the morphological groups ‘atrial septal defects’,‘abnormal atrioventricular valve morphology’, ‘abnormal myocardial trabeculae morphology’, and ‘abnormal outflow tract development’. Centrally in the figure is a hematoxylin–eosin stained frontal section of the heart from a 37‐day human embryo, where tissues affected by the four networks are marked. (Reprinted with permission from Ref 128. Copyright 2010 EMBO and Macmillan Publishers Limited)

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Transcription factor network showing a selection of cardiac relevant genes (nkx 2.5, srf, gata4, mef2a) bound in ChIP‐chip and/or ChIP‐seq, and differentially expressed in RNAi knockdown experiments of the respective factor. Up and downregulation of genes is depicted and occurrence of ChIP binding marked by color‐coded circles. (Reprinted with permission from Ref 5. Copyright 2011 PLOS)

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Heart valve morphogenesis initiates through a process called epithelial‐mesenchymal transition (EMT), in which endocardial cells lose cell–cell contacts (i.e., tight junctions), acquire cell–matrix adhesions, and undergo cytoskeleton rearrangement. The modeling framework encompasses a wide range of spatial scales 10−9 m (e.g., proteins) to 10−3 m (e.g., the primitive heart tube), and temporal scales from 10−6 seconds (e.g., molecular events) to 106 seconds (e.g., weeks of heart development). Multiple XML languages (e.g., SBML, CellML, FieldML) and ontology's are required for multiscale modeling of this complex tissue formation during development. PRO, Protein Ontology; ChEBI, Chemical Entities of Biological Interest; CL, Cell Type Ontology; FMA, Foundational Model of Anatomy; GO‐CC, Gene Ontology Cellular Component; GO‐MF, Gene Ontology Molecular Function; CBO, Cell Behavior Ontology; OPB, Ontology of Physics for Biology; PATO, Phenotype and Trait Ontology; GO‐BP, Gene Ontology Biological Process. (Reprinted with permission from Ref 101. Copyright 2010 IOP Publishing)

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