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Int. J. Mol. Sci. 2018, 19(8), 2335;

Large-Scale Functional Analysis of CRP-Mediated Feed-Forward Loops

Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu 300, Taiwan
Institute of Population Health Sciences, National Health Research Institutes, Miaoli 350, Taiwan
Department of Biological Science and Technology, National Chiao Tung University, Hsinchu 300, Taiwan
Warshel Institute for Computational Biology, The Chinese University of Hong Kong (Shenzhen), Shenzhen 518172, China
School of Science and Engineering, The Chinese University of Hong Kong (Shenzhen), Shenzhen 518172, China
Department of Laboratory Medicine, China Medical University Hospital, Taichung 420, Taiwan
Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
Authors to whom correspondence should be addressed.
Received: 6 June 2018 / Revised: 23 July 2018 / Accepted: 2 August 2018 / Published: 9 August 2018
(This article belongs to the Section Biochemistry)
Full-Text   |   PDF [1951 KB, uploaded 9 August 2018]   |  


Feed-forward loops (FFLs) represent an important and basic network motif to understand specific biological functions. Cyclic-AMP (cAMP) receptor protein (CRP), a transcription factor (TF), mediates catabolite repression and regulates more than 400 genes in response to changes in intracellular concentrations of cAMP in Escherichia coli. CRP participates in some FFLs, such as araBAD and araFGH operons and adapts to fluctuating environmental nutrients, thereby enhancing the survivability of E. coli. Although computational simulations have been conducted to explore the potential functionality of FFLs, a comprehensive study on the functions of all structural types on the basis of in vivo data is lacking. Moreover, the regulatory role of CRP-mediated FFLs (CRP-FFLs) remains obscure. We identified 393 CRP-FFLs in E. coli using EcoCyc and RegulonDB. Dose–response genomic microarray of E. coli revealed dynamic gene expression of each target gene of CRP-FFLs in response to a range of cAMP dosages. All eight types of FFLs were present in CRP regulon with various expression patterns of each CRP-FFL, which were further divided into five functional groups. The microarray and reported regulatory relationships identified 202 CRP-FFLs that were directly regulated by CRP in these eight types of FFLs. Interestingly, 34% (147/432) of genes were directly regulated by CRP and CRP-regulated TFs, which indicates that these CRP-regulated genes were also regulated by other CRP-regulated TFs responding to environmental signals through CRP-FFLs. Furthermore, we applied gene ontology annotation to reveal the biological functions of CRP-FFLs. View Full-Text
Keywords: feed-forward loop (FFL); cAMP receptor protein (CRP); transcription factor (TF) feed-forward loop (FFL); cAMP receptor protein (CRP); transcription factor (TF)

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Yang, C.-D.; Huang, H.-Y.; Shrestha, S.; Chen, Y.-H.; Huang, H.-D.; Tseng, C.-P. Large-Scale Functional Analysis of CRP-Mediated Feed-Forward Loops. Int. J. Mol. Sci. 2018, 19, 2335.

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