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A5770 - Proof of Concept of Eukaryotic Genetic Sensory Response Units in TGF-beta Signaling in Idiopathic Pulmonary Fibrosis
Author Block: Y. I. Balderas-Martinez1, B. Moreno-Quiroga2, M. Negreros3, D. Ledezma-Tejeida2, A. Pardo4, J. Collado-Vides2, M. Selman5; 1Research, CONACYT-Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Ciudad de Mexico, Mexico, 2Computational Genomics Program, Centro de Ciencias Genómicas, Cuernavaca, Mexico, 3Facultad de Ciencias, Universidad Nacional Autónoma de México, CDMX, Mexico, 4Facultad De Ciencias, Univ Nacional Autonoma De Mexico, Mexico, DF, Mexico, 5Inst Nac De Enfermedades Respiratorias, Mexico CP 14080 DF, Mexico.
Rationale: A Genetic Sensory Response Unit (GENSOR Unit, GU) is a concept that represents the concatenated reactions that precede a gene regulation event to produce the adequate cellular response to an initial stimulus. RegulonDB database contains one hundred and eighty-nine GUs in Escherichia coli that summarized almost all the knowledge known in this bacterium in the form of molecular circuits. In this work, we used the GU concept for the first time in eukaryotic systems using TGF-beta signaling as a first approach, applied to the most aggressive interstitial pathology, the Idiopathic Pulmonary Fibrosis (IPF). TGF-beta has been widely studied in IPF, and modeling this network can lead to understanding the design principles of the cellular functions and could help in the development of therapeutic drugs. Methods: The TGF-beta GENSOR unit was manually curated using information from the literature and high-throughput data. We identified the different signals that trigger the pathway in IPF, protein-protein interactions, the transcription factors (TFs) involved, and their DNA binding sites. Then, we looked at the functions of the proteins encoded by the genes regulated by these TFs. This last step is essential to identify the elements that produce regulatory feedbacks. The modeling of the GU circuits was made using CellDesigner. Results: A total of 60 papers of TGF-beta and six high-throughput experiments obtained from GEO, were used to build the GU, they were relevant to dissect the elements of the signal, the associated transcription factors, and the resulting gene expression in IPF versus normal conditions. So far, we have identified three regulatory feedbacks (GUs) that can be considered as the module of a more prominent network which means that they can be updated or assembled with other sub-networks to integrate different signaling pathways. Conclusions: We built a common language between prokaryotic and eukaryotic systems, and we extended the usage of the GENSOR unit concept. The modeling using the idea behind the GUs could be applied to the different regulators to understand the mechanisms that cause disruptions in cellular dynamics and generate diseases. This could help towards a better understanding of diverse biological phenomena through the study of the human interactome.