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Profiling of fasting-feeding dynamics in mouse liver

ABSTRACT: Daily biological rhythms are orchestrated by a combination of the intrinsic circadian clock and external food/feeding-related signals which influence metabolism in health and disease. Understanding how and to which extent both circadian and fasting/feeding rhythms contribute to regulating daily physiology and metabolism is therefore an important ongoing effort. We generated a comprehensive proteomics dataset performing large scale time-series analysis of mouse liver obtained from feeding restricted mice over 2 full days with 16 time points in total, including as a first, a shorter post-feeding sampling-rate focus. Using our label-free absolute quantitative proteomics platform we obtained timelines with very few missing values (>99% data completeness) for over 4000 mouse liver proteoforms using 1D-LC-MS analysis of all time points and replicates (48 samples in total) allowing for robust statistical testing, as well as over 8000 mouse liver proteoforms using online 2D-LC-MS analysis of pooled replicates, providing additional depth of detection. Together our dataset provides an important resource recapitulating and extending current datasets. Our extra focus on post-feeding time points revealed a highly dynamic third metabolic period not previously observed with respect to more classic diurnal rhythmicity, providing an important addition to current knowledge.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

DISEASE(S): Disease Free

SUBMITTER: Richard Sprenger

LAB HEAD: Christer S. Ejsing

PROVIDER: PXD008944 | Pride | 2021-01-22

REPOSITORIES: Pride

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Project description:Over the past decade, genome-wide assays have underscored the broad sweep of circadian gene expression. A substantial fraction of the transcriptome undergoes oscillations in many organisms and tissues, which governs the many biochemical, physiological and behavioral functions under circadian control. Based predominantly on the transcription feedback loops important for core circadian timekeeping, it is commonly assumed that this widespread mRNA cycling reflects circadian transcriptional cycling. To address this issue, we directly measured dynamic changes in mouse liver transcription using Nascent-Seq. Many genes are rhythmically transcribed over the 24h day, which include precursors of several non-coding RNAs as well as the expected set of core clock genes. Surprisingly however, nascent RNA rhythms overlap poorly with mRNA abundance rhythms assayed by RNA-seq. This is because most mouse liver genes with rhythmic mRNA expression manifest poor transcriptional rhythms, indicating a prominent role of post-transcriptional regulation in setting mRNA cycling amplitude. To gain further insight into circadian transcriptional regulation, we also characterized the rhythmic transcription of liver genes targeted by the transcription factors CLOCK and BMAL1; they directly target other core clock genes and sit at the top of the molecular circadian clock hierarchy in mammals. CLK:BMAL1 rhythmically bind at the same discrete phase of the circadian cycle to all target genes, which not surprisingly have a much higher percentage of rhythmic transcription than the genome as a whole. However, there is a surprisingly heterogeneous set of cycling transcription phases of direct target genes, which even include core clock genes. This indicates a disconnect between rhythmic DNA binding and the peak of transcription, which is likely due to other transcription factors that collaborate with CLK:BMAL1. In summary, the application of Nascent-Seq to a mammalian tissue provides surprising insights into the rhythmic control of gene expression and should have broad applications beyond the analysis of circadian rhythms. Mouse liver nascent RNA profile over 6 time points of the 24h light:dark cycle, in duplicate, sequenced using Ilumina GAII (Nascent-Seq); Mouse liver mRNA profile over 6 time points of the 24h light:dark cycle, in duplicate, sequenced using Ilumina HiSeq2000 (RNA-Seq); CLK and BMAL1 DNA binding profile in the mouse liver at ZT8, sequenced along an Input sample using GAII (ChIP-Seq); Mouse liver strand-specific nascent RNA profile over 6 time points of the 24h light:dark cycle, in duplicate, sequenced using Ilumina HiSeq2000 (Strand-specific Nascent-Seq);

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Profiling of fasting-feeding dynamics in mouse liver

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