A proteomics landscape of circadian clock in mouse liver


The mammalian circadian clock includes a “master clock” within the suprachiasmatic nucleus (SCN) of hypothalamus and “peripheral clocks” within other tissues of the body. The “master clock” functions as an “orchestra conductor” to direct “peripheral clocks” through yet-to-be defined pathways, allowing animals to adapt their feeding, activity, and metabolism to predictable daily changes in the environment.

Circadian clocks orchestrate physiological rhythms via the temporal regulation of gene expression to control core clock genes and rhythmic output programs. A network of transcriptional–translational feedback loop comprised of core transcriptional activators (Bmal1 and Clock) and repressors (Per and Cry), to control the rhythmicity in gene expression. Tp53 and Myc, which are well-characterized cancer driver genes, and several multi-functional nuclear receptors (NRs) including Rev-erb, Ror, and Ppar family, have also been shown as important regulators of the circadian clock. These studies demonstrate the critical roles of TFs in regulating circadian rhythm.

Liver plays a fundamental role in circadian clock system. Transcriptome profiling of the liver has demonstrated the circadian variation in the expression of genes related to oxidative metabolism, mitochondrial functions, and amino acid turnover, and that transcriptional regulation drives the circadian mRNA rhythms. In contrast, much less is known on the protein level. With rapid development of analytical techniques, particularly mass spectrometry-based proteomics, it is increasingly feasible to measure proteins in order to understand the diverse biological processes. Recently reported proteome studies in circadian clock of the mouse liver. However, due to the technical limitations in proteomics techniques applied, the dynamics of transcription factors—the key drivers of gene regulations around the circadian clock, were still poorly understood.

It is expected that a hierarchical circadian regulation network might exist, which may include different regulatory layers that facilitate signal transductions around the clock. The TF DNA-binding activities (DBA), which play key roles in regulating transcriptome, would impact the nuclear sub-proteome and in turn, the whole proteome; post-translational modifications, including phosphorylation and ubiquitylation, may also impart another layer of regulation. The complicated relationships among different layers raise many questions that remained to be answered, for instance: (1) how diurnal rhythmic phosphorylation of signaling transduction regulates the rhythm of TF DBA; (2) is there correlation between nuclear TF protein expression and TF DBA; (3) how diurnal rhythmic TF DBA correlates with the diurnal rhythm of downstream genes’ transcription; (4) is there correlation between diurnal rhythms of mRNA expression and protein expression; and (5) how the ubiquitylation system controls the proteome oscillation. Answers to these questions will be informative in portraying a panoramic view of the circadian transcription regulation that governs the temporal switch of physiology in the mouse liver.

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