On schemes of combinatorial transcription logic

Abstract

Cells receive a wide variety of cellular and environmental signals, which are often processed combinatorially to generate specific genetic responses. Here we explore theoretically the potentials and limitations of combinatorial signal integration at the level of cisregulatory transcription control. Our analysis suggests that many complex transcription-control functions of the type encountered in higher eukaryotes are already implementable within the much simpler bacterial transcription system. Using a quantitative model of bacterial transcription and invoking only specific protein-DNA interaction and weak glue-like interaction between regulatory proteins, we show explicit schemes to implement regulatory logic functions of increasing complexity by appropriately selecting the strengths and arranging the relative positions of the relevant protein-binding DNA sequences in the cis-regulatory region. The architectures that emerge are naturally modular and evolvable. Our results suggest that the transcription regulatory apparatus is a ''programmable'' computing machine, belonging formally to the class of Boltzmann machines. Crucial to our results is the ability to regulate gene expression at a distance. In bacteria, this can be achieved for isolated genes via DNA looping controlled by the dimerization of DNA-bound proteins. However, if adopted extensively in the genome, long-distance interaction can cause unintentional intergenic cross talk, a detrimental side effect difficult to overcome by the known bacterial transcription-regulation systems. This may be a key factor limiting the genome-wide adoption of complex transcription control in bacteria. Implications of our findings for combinatorial transcription control in eukaryotes are discussed. Biological organisms ranging from bacteria to humans possess an enormous repertoire of genetic responses to ever-changing combinations of cellular and environmental signals. To a large extent, this repertoire is encoded in complex networks of genes closely regulating the activities of each other. Characterizing and decoding the connectivity of gene regulatory networks has been an outstanding challenge of post-genome molecular biology (1-4). However, unlike integrated circuits, which process information through synchronized cascades of many simple and fast nodes and for which connectivity is the primary source of network complexity, a gene-regulatory network typically consists of only a few tens to hundreds of genes, the expression of which is slow and asynchronous (5). Yet these ''nodes'' are very sophisticated in their capacity to integrate signals: In eukaryotes, each node can be regulated combinatorially, often by four to five other nodes (1, 6), and the regulatory control function can be extremely complex (7). Here we focus primarily on one node of a gene-regulatory network and investigate quantitatively the power and limitations of combinatorial gene regulation in the context of bacterial transcription. We find that the bacterial transcription system is already capable of im...

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