Dataset Information

Transcriptional regulatory logic of the diurnal cycle in the mouse liver.

ABSTRACT: Many organisms exhibit temporal rhythms in gene expression that propel diurnal cycles in physiology. In the liver of mammals, these rhythms are controlled by transcription-translation feedback loops of the core circadian clock and by feeding-fasting cycles. To better understand the regulatory interplay between the circadian clock and feeding rhythms, we mapped DNase I hypersensitive sites (DHSs) in the mouse liver during a diurnal cycle. The intensity of DNase I cleavages cycled at a substantial fraction of all DHSs, suggesting that DHSs harbor regulatory elements that control rhythmic transcription. Using chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq), we found that hypersensitivity cycled in phase with RNA polymerase II (Pol II) loading and H3K27ac histone marks. We then combined the DHSs with temporal Pol II profiles in wild-type (WT) and Bmal1-/- livers to computationally identify transcription factors through which the core clock and feeding-fasting cycles control diurnal rhythms in transcription. While a similar number of mRNAs accumulated rhythmically in Bmal1-/- compared to WT livers, the amplitudes in Bmal1-/- were generally lower. The residual rhythms in Bmal1-/- reflected transcriptional regulators mediating feeding-fasting responses as well as responses to rhythmic systemic signals. Finally, the analysis of DNase I cuts at nucleotide resolution showed dynamically changing footprints consistent with dynamic binding of CLOCK:BMAL1 complexes. Structural modeling suggested that these footprints are driven by a transient heterotetramer binding configuration at peak activity. Together, our temporal DNase I mappings allowed us to decipher the global regulation of diurnal transcription rhythms in the mouse liver.

SUBMITTER: Sobel JA

PROVIDER: S-EPMC5393560 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Transcriptional regulatory logic of the diurnal cycle in the mouse liver.

Sobel Jonathan Aryeh JA Krier Irina I Andersin Teemu T Raghav Sunil S Canella Donatella D Gilardi Federica F Kalantzi Alexandra Styliani AS Rey Guillaume G Weger Benjamin B Gachon Frédéric F Dal Peraro Matteo M Hernandez Nouria N Schibler Ueli U Deplancke Bart B Naef Felix F

PLoS biology 20170417 4

Many organisms exhibit temporal rhythms in gene expression that propel diurnal cycles in physiology. In the liver of mammals, these rhythms are controlled by transcription-translation feedback loops of the core circadian clock and by feeding-fasting cycles. To better understand the regulatory interplay between the circadian clock and feeding rhythms, we mapped DNase I hypersensitive sites (DHSs) in the mouse liver during a diurnal cycle. The intensity of DNase I cleavages cycled at a substantial ...[more]

PMID: 28414715

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Project description:Understanding the kinetics of circadian transcriptional regulation has recently advanced thanks to genome-wide dynamic mapping of RNA Polymerase II, chromatin marks such as histone 3 modifications, and several core clock regulatory factors. To obtain deeper mechanistic insights into the determinant of phase-specific transcription, we here extend previous analyses of the CycliX Consortium by integrating new genome-wide datasets enabling systematic identification of active regulatory regions in the mouse liver. DNase I hypersensitive sites (DHS)-mapping within nuclear chromatin is a powerful method to identify active regulatory elements in the genome. Experiments were performed throughout the diurnal cycle to obtain a temporal map of active regulatory elements. In addition, we quantified H3K27ac, which mark active regulatory regions, throughout the diurnal cycle and RNA Polymerase II using chromatin immunoprecipitation data analysis. DHS were validated as likely regulatory elements by footprinting analyses and overlaps with published ChIP-seq datasets. Analysis of the regions displaying diurnal patterns revealed promoter, transcription start site (TSS)-proximal and TSS-distal elements potentially involved in the regulation of rhythmic gene transcription. Peak phases of DNase I accessibility and H3K27ac levels correlated well with RNA Polymerase II loadings, and regulatory elements oscillated with phases close to those of nearest TSS, which prompted us to use these signals to infer regulatory relationships. Comparisons with results in a Bmal1 -/- genotype (KO) revealed comparable levels of diurnal transcription oscillations likely driven by nutrient and food-entrained rhythms. Using linear modeling, we inferred activities of transcription factors around the clock in WT and KO datasets to reveal that in absence of a functional core circadian clock, FOX transcription factors and glucocorticoid receptor appear to be the main drivers of phase-specific expression. This raises the interesting question of whether light-driven circadian entrainment from the central pacemaker in the SCN acts to counter effect food-related signals.

Dataset Information

Transcriptional regulatory logic of the diurnal cycle in the mouse liver.

Publications

Transcriptional regulatory logic of the diurnal cycle in the mouse liver.

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