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Identifying the entirety of gene regulatory interactions in a biological system offers the possibility to determine the key molecular factors that affect important traits on the level of cells, tissues, and whole organisms. Despite the development of experimental approaches and technologies for identification of direct binding of transcription factors (TFs) to promoter regions of downstream target genes, computational approaches that utilize large compendia of transcriptomics data are still the predominant methods used to predict direct downstream targets of TFs, and thus reconstruct genome-wide gene-regulatory networks (GRNs). These approaches can broadly be categorized into unsupervised and supervised, based on whether data about known, experimentally verified gene-regulatory interactions are used in the process of reconstructing the underlying GRN. Here, we first describe the generic steps of supervised approaches for GRN reconstruction, since they have been recently shown to result in improved accuracy of the resulting networks? We also illustrate how they can be used with data from model organisms to obtain more accurate prediction of gene regulatory interactions.
Recent experiments show that transcription factors (TFs) indeed use the facilitated diffusion mechanism to locate their target sequences on DNA in living bacteria cells: TFs alternate between sliding motion along DNA and relocation events through the cytoplasm. From simulations and theoretical analysis we study the TF-sliding motion for a large section of the DNA-sequence of a common E. coli strain, based on the two-state TF-model with a fast-sliding search state and a recognition state enabling target detection. For the probability to detect the target before dissociating from DNA the TF-search times self-consistently depend heavily on whether or not an auxiliary operator (an accessible sequence similar to the main operator) is present in the genome section. Importantly, within our model the extent to which the interconversion rates between search and recognition states depend on the underlying nucleotide sequence is varied. A moderate dependence maximises the capability to distinguish between the main operator and similar sequences. Moreover, these auxiliary operators serve as starting points for DNA looping with the main operator, yielding a spectrum of target detection times spanning several orders of magnitude. Auxiliary operators are shown to act as funnels facilitating target detection by TFs.