Precise metabolic control is essential for maintaining homeostasis and preventing disease. The transcriptional regulation of metabolism has been intensively studied for decades; however, the focus, thus far, has been on the timing and amplitude of gene expression. Our lab, studying insulin control of liver metabolism, has recently found that the location of gene expression within the tissue can also be regulated to fine tune metabolism. In this talk, our work on bile acid synthesis will be presented: we have found that the repatterning of enzymes that occurs in the absence of insulin favors the production of the toxic bile acids that promote diabetes and associated disorders. We hypothesize that the spatial control of metabolic gene expression represents a novel lens with which to view metabolism that will enable the next generation of therapies to target metabolism.
Universal rules governing expression and activity of metabolic enzymes across the bacterial phylogeny
Bacterial species thrive under a wide variety of conditions. Different species can grow at vastly different rates even for those sharing the same optimal conditions; e.g., Vibrio natriegens grows more than 50% faster than E. coli and B. subtilis in rich medium at 37C. To determine molecular and physiological factors setting the rate of bacterial growth, we employed quantitative proteomics supplemented by measurements of ribosome kinetics to compare the proteome allocation programs of various species chosen across the bacterial phylogeny. We find a nearly identical strategy of allocating ribosomes and biosynthetic enzymes adopted by fast growers despite their very different growth rates and phylogenic distances. In particular, the super-fast growth of V. natriegens arises from fast kinetics of its enzymes, rather than the enzyme amounts. A very different strategy is adopted for slow-growing bacteria such as rhizobium, mycobacterium, and streptomyces. These two distinct strategies can be rationalized by a single evolutionary rule. A plethora of predictions are quantitatively validated.