The nuclear receptor REVERBα is a core component of the circadian clock and proposed to be a dominant regulator of hepatic lipid metabolism. Using antibody-independent ChIP-sequencing of REVERBα in mouse liver, we reveal a high-confidence cistrome and define direct target genes. REVERBα-binding sites are highly enriched for consensus RORE or RevDR2 motifs and overlap with corepressor complex binding. We find no evidence for transcription factor tethering and DNA-binding domain-independent action. Moreover, hepatocyte-specific deletion of Reverbα drives only modest physiological and transcriptional dysregulation, with derepressed target gene enrichment limited to circadian processes. Thus, contrary to previous reports, hepatic REVERBα does not repress lipogenesis under basal conditions. REVERBα control of a more extensive transcriptional program is only revealed under conditions of metabolic perturbation (including mistimed feeding, which is a feature of the global Reverbα^−/− mouse). Repressive action of REVERBα in the liver therefore serves to buffer against metabolic challenge, rather than drive basal rhythmicity in metabolic activity.

核受体 REVERBα 是生物钟的核心成分，被认为是肝脏脂质代谢的主要调节剂。使用小鼠肝脏中 REVERBα 的抗体非依赖性 ChIP 测序，我们揭示了一个高置信度的 cistrome 并定义了直接靶基因。REVERBα 结合位点高度富集共有 RORE 或 RevDR2 基序，并与辅阻遏复合物结合重叠。我们没有发现转录因子束缚和 DNA 结合域独立作用的证据。此外， Reverbα的肝细胞特异性缺失仅驱动适度的生理和转录失调，去抑制的靶基因富集仅限于昼夜节律过程。因此，与之前的报道相反，肝脏 REVERBα 在基础条件下不抑制脂肪生成。REVERBα 对更广泛的转录程序的控制仅在代谢扰动条件下显示（包括不定时喂食，这是全局Reverbα ^-/-小鼠的一个特征）。因此，REVERBα 在肝脏中的抑制作用用于缓冲代谢挑战，而不是驱动代谢活动的基础节律性。