The rhythmic regulation of transcriptional processes is intimately linked to lipid homeostasis, to anticipate daily changes in energy access. The Rev-erbα–HDAC3 complex was previously discovered to execute the rhythmic repression of lipid genes; however, the epigenetic switch that turns on these genes is less clear. Here, we show that genomic recruitment of MRG15, which is encoded by the mortality factor on chromosome 4 (MORF4)-related gene on chromosome 15, displays a significant diurnal rhythm and activates lipid genes in the mouse liver. RNA polymerase II (Pol II) recruitment and histone acetylation correspond to MRG15 binding, and the rhythm is impaired upon MRG15 depletion, establishing MRG15 as a key modulator in global rhythmic transcriptional regulation. MRG15 interacts with the nuclear receptor LRH-1, rather than with known core clock proteins, and is recruited to genomic loci near lipid genes via LRH-1. Blocking of MRG15 by CRISPR targeting or by the FDA-approved drug argatroban, which is an antagonist to MRG15, attenuates liver steatosis. This work highlights MRG15 as a targetable master regulator in the rhythmic regulation of hepatic lipid metabolism.

转录过程的节律性调节与脂质稳态密切相关，以预测能量获取的每日变化。先前发现Rev-erbα–HDAC3复合物可对脂质基因进行节律性抑制。然而，开启这些基因的表观遗传开关还不清楚。在这里，我们显示了MRG15的基因组募集，该募集由4号染色体上的死亡因子（MORF415号染色体上的）相关基因表现出明显的昼夜节律并激活小鼠肝脏中的脂质基因。RNA聚合酶II（Pol II）募集和组蛋白乙酰化对应于MRG15结合，并且MRG15耗尽后节律受损，从而确立了MRG15作为全局节律性转录调控的关键调节剂。MRG15与核受体LRH-1相互作用，而不是与已知的核心时钟蛋白相互作用，并通过LRH-1被募集到脂质基因附近的基因组位点。CRISPR靶向或FDA批准的药物argatroban对MRG15的阻断可减弱肝脂肪变性，而该药物是MRG15的拮抗剂。这项工作强调了MRG15作为肝脂质代谢节律性调节中的可靶向主调节剂。