Oscillating and stable genome topologies underlie hepatic physiological rhythms during the circadian cycle

Autoři: Jérôme Mermet aff001;  Jake Yeung aff001;  Felix Naef aff001
Působiště autorů: The Institute of Bioengineering (IBI), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland aff001
Vyšlo v časopise: Oscillating and stable genome topologies underlie hepatic physiological rhythms during the circadian cycle. PLoS Genet 17(2): e1009350. doi:10.1371/journal.pgen.1009350
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1009350


The circadian clock drives extensive temporal gene expression programs controlling daily changes in behavior and physiology. In mouse liver, transcription factors dynamics, chromatin modifications, and RNA Polymerase II (PolII) activity oscillate throughout the 24-hour (24h) day, regulating the rhythmic synthesis of thousands of transcripts. Also, 24h rhythms in gene promoter-enhancer chromatin looping accompany rhythmic mRNA synthesis. However, how chromatin organization impinges on temporal transcription and liver physiology remains unclear. Here, we applied time-resolved chromosome conformation capture (4C-seq) in livers of WT and arrhythmic Bmal1 knockout mice. In WT, we observed 24h oscillations in promoter-enhancer loops at multiple loci including the core-clock genes Period1, Period2 and Bmal1. In addition, we detected rhythmic PolII activity, chromatin modifications and transcription involving stable chromatin loops at clock-output gene promoters representing key liver function such as glucose metabolism and detoxification. Intriguingly, these contacts persisted in clock-impaired mice in which both PolII activity and chromatin marks no longer oscillated. Finally, we observed chromatin interaction hubs connecting neighbouring genes showing coherent transcription regulation across genotypes. Thus, both clock-controlled and clock-independent chromatin topology underlie rhythmic regulation of liver physiology.

Klíčová slova:

Circadian oscillators – DNA transcription – Genetic oscillators – Genomic signal processing – Hypersensitivity – Chromatin – Mammalian genomics – Transcriptional control


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