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Sustained-input switches for transcription factors and microRNAs are central building blocks of eukaryotic gene circuits

Publication Online:
Megraw M, Mukherjee S, Ohler U. (2013). Sustained-input switches for transcription factors and microRNAs are central building blocks of eukaryotic gene circuits. Genome Biology.

About this study: 
In this study we present WaRSwap (Weighted and Reverse Swap sampling), a network randomization method that for the first time provides a practical algorithm for network motif discovery in large multi-layer networks that include Transcription Factors (TFs), microRNAs (miRNAs), and non-TF protein coding genes. The algorithm is applicable to systems with tens of thousands of genes, while accounting for critical aspects of regulatory networks, including self-loops, large hubs, and target rearrangements. We apply the method on a network from Arabidopsis thaliana, a particularly amenable model organism for which we identify all significant 2-and 3-node motifs. Because our method is applicable to circuits with self-loops, we identify prevalent autoregulatory gene circuits long associated with developmental patterning. Among motifs containing both TFs and miRNAs, the miRNA-mediated feed forward loop is a predominant theme, but our results suggest that this pulse-generating circuit may be specific to tightly regulated TF and miRNA binding. Finally, we identify a gene circuit capable of creating a sustained input switch for a downstream TF or miRNA that is robustly embedded into the structure of our biological network. Our analysis supports the hypothesis that sub-circuits associated with development are dominant across large multi-cellular genetic systems because of the need for reliable spatio-temporal pattern formation in complex organisms.

WaRSwap Code
We provide our implementation of the WaRSwap algorithm in R as publicly available open source code under the GNU Public License (GPL).

FANMOD modified versions
We make available the modified command-line versions of FANMOD that we used in running edge-switching randomizations in parallel, enumerating subgraphs, and performing randomization comparisons on small test networks.

Sun Grid Engine parallelizations
Both WaRSwap and FANMOD parallelizations were run on Sun Grid Engine; we make the script sets available for others to use and adapt.

Our TF binding site scanning software used in this work is also currently available under the GPL at as the Scanner Toolset.