A Persistence Detector for Metabolic Network Rewiring in an Animal.

Summary Biological systems must possess mechanisms that prevent inappropriate responses to spurious environmental inputs. Caenorhabditis elegans has two breakdown pathways for the short-chain fatty acid propionate: a canonical, vitamin B12-dependent pathway and a propionate shunt that is used when vitamin B12 levels are low. The shunt pathway is kept off when there is sufficient flux through the canonical pathway, likely to avoid generating shunt-specific toxic intermediates. Here, we discovered a transcriptional regulatory circuit that activates shunt gene expression upon propionate buildup. Nuclear hormone receptor 10 (NHR-10) and NHR-68 function together as a "persistence detector" in a type 1, coherent feed-forward loop with an AND-logic gate to delay shunt activation upon propionate accumulation and to avoid spurious shunt activation in response to a non-sustained pulse of propionate. Together, our findings identify a persistence detector in an animal, which transcriptionally rewires propionate metabolism to maintain homeostasis. Graphical Abstract Highlights • A transcriptional persistence detector activates propionate shunt only when needed • Persistence detection prevents generation of toxic shunt intermediates • nhr-10 and nhr-68 are persistence detectors in a feed-forward loop with AND-logic gate • nhr-68 autoactivates and modeling shows that this can provide circuit tunability Bulcha et al. discover a transcriptional persistence detector composed of a type 1 coherent feed-forward loop with an AND-logic gate that rewires propionate metabolism in C. elegans. [ABSTRACT FROM AUTHOR]