Identification of tissue-specific cis-regulatory modules based on interactions between transcription factors

The conservation-independent approach is based on an empirical potential energy between interacting transcription factors (TFs). In this analysis, the potential energy is defined as a function of the number of TF interactions in a genomic region and the strength of the interactions. By identifying sets of interacting TFs, the analysis locates regions enriched with the binding sites of these interacting TFs. We applied this approach to 30 human tissues and identified 6232 putative cis-regulatory modules (CRMs) regulating 2130 tissue-specific genes. Interestingly, some genes appear to be regulated by different CRMs in different tissues. Known regulatory regions are highly enriched in our predicted CRMs. In addition, DNase I hypersensitive sites, which tend to be associated with active regulatory regions, significantly overlap with the predicted CRMs, but not with more conserved regions. We also find that conserved and non-conserved CRMs regulate distinct gene groups. Conserved CRMs control more essential genes and genes involved in fundamental cellular activities such as transcription. In contrast, non-conserved CRMs, in general, regulate more non-essential genes, such as genes related to neural activity.These results demonstrate that identifying relevant sets of binding motifs can help in the mapping of DNA regulatory regions, and suggest that non-conserved CRMs play an important role in gene regulation.Transcriptional regulation is a key component of gene regulation, which itself plays a major role in all forms of cellular differentiation and function. To understand the mechanisms that regulate gene expression, it is important to identify and define the network of cis-acting DNA regulatory elements, which can be viewed as the regulatory code wired within the genome. The code itself is executed through transcription factors (TFs), which determine which set of genes will be expressed. Because the cis-regulatory elements are usually short and degenerate, distinguishing