Deciphering the genome's regulatory code: the many languages of DNA.

The generation of patterns and the diversity of cell types in a multicellular organism require differential gene regulation. At the heart of this process are enhancers or cis-regulatory modules (CRMs), genomic regions that are bound by transcription factors (TFs) that control spatio-temporal gene expression in developmental networks. To date, only a few CRMs have been studied in detail and the underlying cis-regulatory code is not well understood. Here, we review recent progress on the genome-wide identification of CRMs with chromatin immunoprecipitation of TF-DNA complexes followed by microarrays (ChIP-on-chip). We focus on two computational approaches that have succeeded in predicting the expression pattern driven by a CRM either based on TF binding site preferences and their expression levels, or quantitative analysis of CRM occupancy by key TFs. We also discuss the current limits of these methods and highlight some of the key problems that have to be solved to gain a more complete understanding of the structure and function of CRMs.