SummaryActive mechanisms exist to prevent transcription that is uncoupled from translation in the protein-coding genes of bacteria, as exemplified by the phenomenon of nonsense polarity. Bacterial transcription-translation coupling may be viewed as one among several co-transcriptional processes, including those for mRNA processing and export in the eukaryotes, that operate in the various life forms to render the nascent transcript unavailable for formation of otherwise deleterious R-loops in the genome.

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Small molecules generally activate or inhibit gene transcription as externally added substrates or as internally accumulated endproducts, respectively. Rarely has a connection been made that links an intracellular intermediary metabolite as a signal of gene expression. We report that a perturbation in the critical step of a metabolic pathway-the D-galactose amphibolic pathwaychanges the dynamics of the pathways leading to accumulation of the intermediary metabolite UDP-galactose. This accumulation causes cell stress and transduces signals that alter gene expression so as to cope with the stress by restoring balance in the metabolite pool. This underscores the importance of studying the global effects of alterations in the level of intermediary metabolites in causing stress and coping with it by transducing signals to genes to reach a stable state of equilibrium (homeostasis). Such studies are an essential component in the integration of metabolomics, proteomics, and transcriptomics.galactose metabolism ͉ gene signals ͉ intracellular stress ͉ tiling arrays A cell is capable of carrying out thousands of chemical reactions to make or break compounds of different kinds (metabolites). To achieve proper balance in its chemical constituents, these reactions are programmed in time. If there is either a lack or an excess of an important metabolite, it could create stress. The cell is expected to take care of such a stress in two ways: (i) The first is a quick fix, which occurs at a biochemical level by activation or inhibition of the catalytic activities of enzymes by metabolites so as to restore homeostasis to the chemical milieu of the cell. (ii) The second is a long term solution in which the synthesis of enzymes or proteins whose presence or absence causes the chemical imbalance is turned off or on. These control mechanisms occur at different levels, but the primary level of a metabolite signal is perceived at the level of transcription. So far, the literature describes two classes of metabolites that signal gene transcription: (i) a substrate of an enzymatic pathway induces the synthesis of the enzymes of that pathway (usually catabolic), or (ii) the end-product of a pathway represses the synthesis of the enzymes of the pathway (usually anabolic). However, except for protein-modifying metabolites, e.g., acetylCoA (1, 2) or acetyl-phosphate (3), intermediary metabolites signaling even a specific gene transcription have been reported only in very few cases (4-6). We propose that gene regulation mediated by intermediary metabolites may be more widespread than previously perceived, particularly with respect to the regulation of genes encoding enzymes of amphibolic pathways, in which catabolic pathways overlap with or connect to anabolic pathways. Knowledge of the nature and extent of this type of regulation in an organism is needed for a complete understanding of the genetic regulatory network of cells. We explored one such metabolic intermediate, UDP-galactose, which we found not only sends signals to specific genes to...