Abstract

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.

Highlights

  • Human behaviour and physiology have adapted to daily recurring inputs from the environment

  • Thousands of genes, including ones belonging to the central clock, lipid and glucose metabolism, as well as detoxification are expressed with a 24h period

  • We monitored DNA contacts across the circadian cycle involving the promoters of genes playing key roles in the daily physiology of the mouse liver

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Summary

Introduction

Human behaviour and physiology have adapted to daily recurring inputs from the environment. The circadian clock is molecularly encoded and relies on interlocked feedback loops of gene function ticking in virtually every cell of the body [2]. In this model, BMAL1 and CLOCK transcription factors (TF) regulate the expression of their own repressors including Period (Period, Period2) and Cryptochrome (Cryptochrome and Cryprochrome2) genes [3]. Clock-based and organspecific TF activities interweave to regulate tissue-specific rhythms in transcriptional programs and physiology [4,5]. In mouse liver, TF binding as well as chromatin modifications and accessibility and PolII activity fluctuate genome-wide and drive the rhythmic expression of thousands of genes important for hepatic functions [6,7,8]. Rhythms in post-transcriptional mechanisms can drive oscillations in the abundance and activity of gene products [9,10,11,12]

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