Transcription factor activity rhythms and tissue-specific chromatin interactions explain circadian gene expression across organs. Mus musculus

Temporal control of physiology requires the interplay between gene networks involved in daily timekeeping and tissue function across different organs. How the circadian clock interweaves with tissue-specific transcriptional programs is poorly understood. Here we dissected temporal and tissue-specific regulation at multiple layers of gene regulation by examining mouse tissues with an intact or disrupted clock over time. Integrated analysis uncovered two distinct regulatory modes underlying tissue-specific rhythms: (1) tissue-specific rhythmically active transcription factors that notably regulated feeding-fasting related rhythms in liver and sodium homeostasis in kidney; (2) co-localized binding of clock and tissue-specific transcription factors at distal enhancers. Chromosome conformation capture (4C-Seq) in liver and kidney identified liver-specific chromatin loops that recruited clock transcription factors to promoters in a tissue-specific manner. Furthermore, this looping was remarkably promoter-specific, nearby alternative promoters with differential temporal outputs formed distinct chromatin loops. These findings suggest that precise chromatin folding enables the clock to regulate rhythmic transcription of specific promoters to output temporal transcriptional programs tailored to different tissues. Overall design: RNA-Seq from total RNA of mouse kidney during the dirunal cycle. Time-series mRNA profiles of wild type (WT) and Bmal -/- mice under ad libitum and night restriced feeding regimen were generated by deep sequencing. Chromosome conformation capture (4C-Seq) in liver and kidney was also performed.