Biology subjects

Weger, B. D.

Publications and source records attributed to Weger, B. D..

3 recordsLinked to original sources

bioRxiv2022

A role for caveolar proteins in regulation of the circadian clock

Caveolae are specialized invaginations of the plasma membrane that are formed by the co-assembly of caveolin integral membrane proteins and a cytoplasmic cavin coat complex. Previous work has proposed an interaction of the cavin coat protein, CAVIN3, with the key circadian clock protein, PER2. Here we show that cavin proteins can play a role in the regulation of the circadian clock by external stimuli. Loss of Cavin1 in mice caused a shortening of the free-running period of locomotor activity. CAVIN1 and CAVIN3 were found to play a central role in core clock dynamics with either cavin protein directly interacting with PER2 and their perturbation leading to significant disruption in core clock mRNA expression and CRY1 protein oscillation. In cells, association of cavins and PER2 was increased upon caveola disassembly caused by oxidative stress or by calcium influx, stimuli linked to circadian clock regulation. We thus propose that the caveola system can play a modulatory role in circadian regulation through the cavin proteins.

cell biology↗

bioRxiv2022

Mice with humanized livers reveal the involvement of hepatocyte circadian clocks in rhythmic behavior and physiology

The circadian clock is an evolutionarily acquired gene network that synchronizes physiological processes to adapt homeostasis to the succession of day and night. While most mammalian cells have a circadian clock, their synchronization at the body-level depends on a central pacemaker located in the suprachiasmatic nuclei of the hypothalamus that integrates light signals. However, peripheral organs are also synchronized by feeding cues that can uncoupled them from the central pacemaker. Nevertheless, the potential feedback of peripheral signals on the central clock remains poorly characterized. To discover whether peripheral organ circadian clocks may affect the central pacemaker, we used a chimeric model in which mouse hepatocytes were replaced by human hepatocytes. These human hepatocytes showed a specific rhythmic physiology caused by their blunted response to mouse systemic signals. Strikingly, mouse liver humanization reprogrammed the liver diurnal gene expression and modified the phase of the circadian clock. The phase advance was also reflected in the muscle as well as the entire rhythmic physiology of the animals, indicating an impact on the circadian function of the central clock. Like mice with a deficient central clock, the humanized animals shifted their rhythmic physiology more rapidly to the light phase under day feeding. Our results indicate that peripheral clocks may affect the central pacemaker and offer new perspectives to understand the impact of peripheral clocks on the global circadian physiology.

physiology↗

bioRxiv2021

Comprehensive analysis of the circadian nuclear and cytoplasmic transcriptome in mouse liver

In eukaryotes, RNA is synthesised in the nucleus, spliced, and exported to the cytoplasm where it is translated and finally degraded. Any of these steps could be subject to temporal regulation during the circadian cycle, resulting in daily fluctuations of RNA accumulation and affecting the distribution of transcripts in different subcellular compartments. Our study analysed the nuclear and cytoplasmic, poly(A) and total transcriptomes of mouse livers collected over the course of a day. These data provide a genome-wide temporal inventory of enrichment in subcellular RNA, and revealed specific signatures of splicing, nuclear export and cytoplasmic mRNA stability related to transcript and gene lengths. Combined with a mathematical model describing rhythmic RNA profiles, we could test the rhythmicity of export rates and cytoplasmic degradation rates of approximately 1400 genes. With nuclear export times usually much shorter than cytoplasmic half-lives, we found that nuclear export contributes to the modulation and generation of rhythmic profiles of 10% of the cycling nuclear mRNAs. This study contributes to a better understanding of the dynamic regulation of the transcriptome during the day-night cycle.

systems biology↗