Genomic Convergence among ERRα, PROX1, and BMAL1 in the Control of Metabolic Clock Outputs

Metabolic homeostasis and circadian rhythms are closely intertwined biological processes. Nuclear receptors, as sensors of hormonal and nutrient status, are actively implicated in maintaining this physiological relationship. Although the orphan nuclear receptor estrogen-related receptor α (ERRα, NR3B1) plays a central role in the control of energy metabolism and its expression is known to be cyclic in the liver, its role in temporal control of metabolic networks is unknown. Here we report that ERRα directly regulates all major components of the molecular clock. ERRα-null mice also display deregulated locomotor activity rhythms and circadian period lengths under free-running conditions, as well as altered circulating diurnal bile acid and lipid profiles. In addition, the ERRα-null mice exhibit time-dependent hypoglycemia and hypoinsulinemia, suggesting a role for ERRα in modulating insulin sensitivity and glucose handling during the 24-hour light/dark cycle. We also provide evidence that the newly identified ERRα corepressor PROX1 is implicated in rhythmic control of metabolic outputs. To help uncover the molecular basis of these phenotypes, we performed genome-wide location analyses of binding events by ERRα, PROX1, and BMAL1, an integral component of the molecular clock. These studies revealed the existence of transcriptional regulatory loops among ERRα, PROX1, and BMAL1, as well as extensive overlaps in their target genes, implicating these three factors in the control of clock and metabolic gene networks in the liver. Genomic convergence of ERRα, PROX1, and BMAL1 transcriptional activity thus identified a novel node in the molecular circuitry controlling the daily timing of metabolic processes.

代谢稳态与昼夜节律是紧密互作的生物学过程。核受体作为激素与营养状态的感受器，积极参与维持这一生理关联。尽管孤儿核受体雌激素相关受体α（estrogen-related receptor α, ERRα, NR3B1）在能量代谢调控中发挥核心作用，且已知其在肝脏中的表达呈节律性，但它在代谢网络时序调控中的功能仍未明确。本研究发现ERRα可直接调控分子钟的所有核心组分。ERRα基因敲除小鼠在自由运行条件下表现出运动活动节律紊乱、昼夜周期时长异常，同时循环胆汁酸与脂质的昼夜分布谱发生改变。此外，ERRα基因敲除小鼠呈现出时间依赖性的低血糖与低胰岛素血症，提示ERRα在24小时光暗周期中参与调控胰岛素敏感性与葡萄糖代谢。本研究还证实，新发现的ERRα辅阻遏因子PROX1参与代谢输出的节律调控。为阐明这些表型的分子机制，我们对ERRα、PROX1以及分子钟核心组分BMAL1的全基因组结合事件进行了定位分析。这些研究揭示了ERRα、PROX1与BMAL1之间存在转录调控环路，且三者的靶基因存在广泛重叠，表明这三个因子共同参与肝脏中分子钟与代谢基因网络的调控。综上，ERRα、PROX1与BMAL1转录活性的基因组交汇位点，为调控代谢过程每日时序的分子环路发现了全新的调控节点。