Mammalian physiology exhibits 24-hour cyclicity due to circadian rhythms of gene expression controlled by transcription factors (TF) that comprise molecular clocks. Core clock TFs bind to the genome at enhancer sequences to regulate circadian gene expression, but not all binding sites are equally functional. Here we demonstrate that circadian gene expression in mouse liver is controlled by rhythmic chromatin interactions between enhancers and promoters. Rev-erbα, a core repressive TF of the clock, opposes functional loop formation between Rev-erbα-regulated enhancers and circadian target gene promoters by recruitment of the NCoR-HDAC3 corepressor complex, histone deacetylation, and eviction of the elongation factor BRD4 and the looping factor MED1. Thus, a repressive arm of the molecular clock operates by rhythmically modulating chromatin loops to control circadian gene transcription.

Abstract All biological processes, living organisms, and ecosystems have evolved with the Sun that confers a 24-hour periodicity to life on Earth. Circadian rhythms arose from evolutionary needs to maximize daily organismal fitness by enabling organisms to mount anticipatory and adaptive responses to recurrent light-dark cycles and associated environmental changes. The clock is a conserved feature in nearly all forms of life, ranging from prokaryotes to virtually every cell of multicellular eukaryotes. The mammalian clock comprises transcription factors interlocked in negative feedback loops, which generate circadian expression of genes that coordinate rhythmic physiology. In this review, we highlight previous and recent studies that have advanced our understanding of the transcriptional architecture of the mammalian clock, with a specific focus on epigenetic mechanisms, transcriptomics, and 3-dimensional chromatin architecture. In addition, we discuss reciprocal ways in which the clock and metabolism regulate each other to generate metabolic rhythms. We also highlight implications of circadian biology in human health, ranging from genetic and environment disruptions of the clock to novel therapeutic opportunities for circadian medicine. Finally, we explore remaining fundamental questions and future challenges to advancing the field forward.

REV-ERB nuclear receptors are potent transcriptional repressors that play an important role in the core mammalian molecular clock and metabolism. Deletion of both REV-ERBα and its largely redundant isoform REV-ERBβ in a murine tissue-specific manner have shed light on their specific functions in clock mechanisms and circadian metabolism. This review highlights recent findings that establish REV-ERBs as crucial circadian timekeepers in a variety of tissues, regulating overlapping and distinct processes that maintain normal physiology and protect from metabolic dysfunction.