Transcriptional programs: Modelling higher order structure in transcriptional control

We applied our method to putative regulatory regions of 18,445 Mus musculus genes. We discovered just 68 transcriptional programs that effectively summarised the action of 149 transcription factors on these genes. Several of these programs were significantly enriched for known biological processes and signalling pathways. One transcriptional program has a significant overlap with a reference set of cell cycle specific transcription factors.Our method is able to pick out higher order structure from noisy sequence analyses. The transcriptional programs it identifies potentially represent common mechanisms of regulatory control across the genome. It simultaneously predicts which genes are co-regulated and which sets of transcription factors cooperate to achieve this co-regulation. The programs we discovered enable biologists to choose new genes and transcription factors to study in specific transcriptional regulatory systems.Organisms ranging in complexity from bacteria to higher eukaryotes are able to react and adapt to environmental and cellular signals. These responses are often encoded as complex gene regulatory networks. In these networks the expression of a gene's products is regulated by the activity of other genes. Although regulation can occur at many levels, we focus on transcriptional regulation, one of the most important and pervasive methods of regulation in eukaryotes. Transcriptional regulation occurs when certain gene products, transcription factors (TFs), bind to the DNA at binding sites (TFBSs) and affect the transcription of the regulated gene by modulation of the RNA polymerase complex. TFBSs often appear in clusters or cis-regulatory modules (CRMs), presumably to enable interactions between TFs binding there.TFs do not work in isolation from each other. Particularly in higher organisms, combinatorial operations are often necessary for the response of a cell to external stimuli or developmental programs. Such a response is frequently implemented as