Biological code breaking in the 21st century

Mol Syst Biol. 2: 2006.0018Just as early molecular biologists made the conceptual leap from the unique structure of DNA—with its precise sequence of nucleotides and complementary strands—to a theoretical and empirical solution to the genetic coding problem, four decades later a new generation of biologists is tackling a similar scientific challenge, this time of even greater complexity. How do DNA sequences specify the coordinated temporal and spatial expression patterns of functionally related genes throughout the life cycle of an organism? Whereas recognition of the fundamental relationships among DNA, RNA and protein provided the impetus for unraveling the genetic code, comparative sequence analysis, gene expression profiles, transcription factor binding site specificities, chromatin immunoprecipitation and powerful computational tools to analyze and integrate these diverse data sets are priming the way for deciphering the cis ‐regulatory codes that direct specific gene expression patterns. A paper by Ukkonen, Taipale and co‐workers (Hallikas et al , 2006) in a recent issue of Cell is among the latest important contributions to this quest.Detailed studies of transcriptional cis ‐regulatory elements from different species and biological contexts have yielded the general view that promoters and enhancers are modular; that is, they consist of closely clustered binding sites for one or more transcription factors. This structure facilitates combinatorial interactions among transcription factors, a mechanism that plays an essential role in generating gene expression specificity and diversity in metazoans (Levine and Tjian, 2003). Modularity also enables cis ‐regulatory elements to integrate convergent inputs from intrinsic factors—acquired early in the development of a cell—with later‐acting extrinsic signals (Carroll et al , 2005). Superimposed on this complexity is the need for a cell to simultaneously express genes encoding proteins with related functions. Perhaps the most economical solution to the latter problem is for coexpressed genes to contain similar cis …