Program in Systems Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Program in Systems Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Cell Rep. 2019 Jan 8;26(2):460-468.e4. doi: 10.1016/j.celrep.2018.12.064.
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.
生物系统必须具备防止对虚假环境输入产生不当反应的机制。秀丽隐杆线虫有两种短链脂肪酸丙酸的分解途径：一种是典型的、依赖维生素 B12 的途径，另一种是当维生素 B12 水平较低时使用的丙酸分流途径。当典型途径有足够的通量时，分流途径就会关闭，这可能是为了避免产生分流特异性的有毒中间体。在这里，我们发现了一个转录调控回路，当丙酸积累时，它会激活分流基因的表达。核激素受体 10（NHR-10）和 NHR-68 一起作为一个“持久性探测器”，在一个具有 AND 逻辑门的 1 型一致前馈环中协同作用，以延迟丙酸积累时的分流激活，并避免对非持续丙酸脉冲的虚假分流激活。总之，我们的研究结果在动物中鉴定出了一个持久性探测器，它通过转录重布线丙酸代谢来维持体内平衡。
