The Salk Institute for Biological Studies, La Jolla, California
A cancer researcher ponders a fundamental connection between nutrients and gene expression.
Nutrient availability to single-celled organisms varies according to their environment, and proteins in the cell that sense nutrient levels alter gene expression to increase uptake and use of specific metabolites to fuel cellular processes. Conversely, most cells in multicellular organisms are exposed to constant nutrient levels by the bloodstream, and so far there are few examples of metabolism being directly coupled to the control of gene expression.
A recent paper by Craig Thompson and his colleagues at the University of Pennsylvania in Philadelphia uncovers a direct connection between a well-known metabolic enzyme — ATP citrate lyase (ACL) — and changes in gene expression (K. E. Wellen et al. Science 324, 1076–1080; 2009). Through a chain of reactions, ACL influences the functioning of the histones, proteins that package lengths of DNA — and unpackage them for ‘reading’. This means that there is a basic — and surprising — relationship between cell glucose levels and gene expression.
We don’t yet know how metabolic challenges — for example, fasting — in whole organisms affect ACL levels or activity. But we do know that some of the same proteins that increase tumour growth also modify ACL by attaching phosphorus.
It is likely that we are just at the tip of the iceberg in terms of our understanding of the molecular basis of how metabolic inputs dictate gene-expression changes in mammalian cells. Future studies using genetic models of ACL loss in distinct mouse tissues, as well as chemical inhibitors of the enzyme, will help to elucidate in which contexts it is critical for gene-expression changes in the whole organism. Moreover, our knowledge of this metabolic linchpin may provide a therapeutic window for the treatment of certain forms of cancer, almost all of which undergo metabolic adaptation.