Noisy information processing through transcriptional regulation

Cells must respond to environmental changes to remain viable, yet the information they receive is often noisy. Through a biochemical implementation of Bayes's rule, we show that genetic networks can act as inference modules, inferring from intracellular conditions the likely state of the extracellular environment and regulating gene expression appropriately. By considering a two-state environment, either poor or rich in nutrients, we show that promoter occupancy is proportional to the (posterior) probability of the high nutrient state given current intracellular information. We demonstrate that single-gene networks inferring and responding to a high environmental state infer best when negatively controlled, and those inferring and responding to a low environmental state infer best when positively controlled. Our interpretation is supported by experimental data from the lac operon and should provide a basis for both understanding more complex cellular decision-making and designing synthetic inference circuits.     

From the Cover: Circadian acetylome reveals regulation of mitochondrial metabolic pathways

The circadian clock is constituted by a complex molecular network that integrates a number of regulatory cues needed to maintain organismal homeostasis. To this effect, posttranslational modifications of clock proteins modulate circadian rhythms and are thought to convert physiological signals into changes in protein regulatory function. To explore reversible lysine acetylation that is dependent on the clock, we have characterized the circadian acetylome in WT and Clock-deficient (Clock^−/−) mouse liver by quantitative mass spectrometry. Our analysis revealed that a number of mitochondrial proteins involved in metabolic pathways are heavily influenced by clock-driven acetylation. Pathways such as glycolysis/gluconeogenesis, citric acid cycle, amino acid metabolism, and fatty acid metabolism were found to be highly enriched hits. The significant number of metabolic pathways whose protein acetylation profile is altered in Clock^−/− mice prompted us to link the acetylome to the circadian metabolome previously characterized in our laboratory. Changes in enzyme acetylation over the circadian cycle and the link to metabolite levels are discussed, revealing biological implications connecting the circadian clock to cellular metabolic state.     

Tissue-specific dysregulation of 11beta-hydroxysteroid dehydrogenase type 1 and pathogenesis of the metabolic syndrome

Glucocorticoids are important regulators of glucose, lipid and protein metabolism, acting mainly in the liver, adipose tissue and muscle. Chronic glucocorticoid excess is associated with clinical features, such as insulin resistance, visceral obesity, hypertension, and dyslipidemia, which also represent the classical hallmarks of the metabolic syndrome. Elevenbeta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1), a key intracellular enzyme which catalyses the conversion of inactive cortisone to active cortisol, has been implicated in the development of the metabolic syndrome. The shift of this reaction towards cortisol generation may lead to tissutal overexposure to glucocorticoids even with normal circulating cortisol levels. The most robust evidence in support of a pathogenetic role of this enzyme in the development of the metabolic syndrome has been reported in experimental animals, whereas results of human studies are less convincing with several case control and cross-sectional studies showing an association between with 11beta-HSD-1 setpoint and individual features of the metabolic syndrome. However, recent data suggest a tissue-specific rather than systemic alteration of this shuttle, with down-regulation in liver but up-regulation in adipose tissue and skeletal muscle of obese subjects. New techniques based on direct tissutal estimates of cortisol/cortisone ratios are clearly needed to precisely assess the role of enzyme in all target tissues. If confirmed, these results would prompt the development of selective and tissue-specific 11beta-HSD-1 inhibitors to decrease insulin resistance and treat the metabolic syndrome, thus contrasting the harmful effects of glucocorticoid excess in peripheral tissues.     

Optimizing bioconversion pathways through systems analysis and metabolic engineering

We demonstrate a general approach for metabolic engineering of biocatalytic systems comprising the uses of a chemostat for strain improvement and radioisotopic tracers for the quantification of pathway fluxes. Flux determination allows the identification of target pathways for modification as validated by subsequent overexpression of the corresponding gene. We demonstrate this method in the indene bioconversion network of Rhodococcus modified for the overproduction of 1,2-indandiol, a key precursor for the AIDS drug Crixivan.