bims-ciryme 2023-07-02 papers

Genes Dev. 2023 Jun 26.

Circadian mechanisms in adipose tissue bioenergetics and plasticity.

The circadian clock plays an essential role in coordinating feeding and metabolic rhythms with the light/dark cycle. Disruption of clocks is associated with increased adiposity and metabolic disorders, whereas aligning feeding time with cell-autonomous rhythms in metabolism improves health. Here, we provide a comprehensive overview of recent literature in adipose tissue biology as well as our understanding of molecular mechanisms underlying the circadian regulation of transcription, metabolism, and inflammation in adipose tissue. We highlight recent efforts to uncover the mechanistic links between clocks and adipocyte metabolism, as well as its application to dietary and behavioral interventions to improve health and mitigate obesity.

Keywords: adipocyte; adipose tissue; circadian clock; circadian rhythms; inflammation; metabolism; plasticity; thermogenesis; transcription

DOI: https://doi.org/10.1101/gad.350759.123

J Cell Biol. 2023 Sep 04. pii: e202209120. [Epub ahead of print]222(9):

Mechanical control of the mammalian circadian clock via YAP/TAZ and TEAD.

Juan F Abenza, Leone Rossetti, Malèke Mouelhi, Javier Burgués, Ion Andreu, Keith Kennedy, Pere Roca-Cusachs, Santiago Marco, Jordi García-Ojalvo, Xavier Trepat.

Autonomous circadian clocks exist in nearly every mammalian cell type. These cellular clocks are subjected to a multilayered regulation sensitive to the mechanochemical cell microenvironment. Whereas the biochemical signaling that controls the cellular circadian clock is increasingly well understood, mechanisms underlying regulation by mechanical cues are largely unknown. Here we show that the fibroblast circadian clock is mechanically regulated through YAP/TAZ nuclear levels. We use high-throughput analysis of single-cell circadian rhythms and apply controlled mechanical, biochemical, and genetic perturbations to study the expression of the clock gene Rev-erbα. We observe that Rev-erbα circadian oscillations are disrupted with YAP/TAZ nuclear translocation. By targeted mutations and overexpression of YAP/TAZ, we show that this mechanobiological regulation, which also impacts core components of the clock such as Bmal1 and Cry1, depends on the binding of YAP/TAZ to the transcriptional effector TEAD. This mechanism could explain the impairment of circadian rhythms observed when YAP/TAZ activity is upregulated, as in cancer and aging.

DOI: https://doi.org/10.1083/jcb.202209120

Front Neurosci. 2023 ;17 1166137

Cry1 expression during postnatal development is critical for the establishment of normal circadian period.

Aaron E Schirmer, Vivek Kumar, Andrew Schook, Eun Joo Song, Michael S Marshall, Joseph S Takahashi.

The mammalian circadian system generates an approximate 24-h rhythm through a complex autoregulatory feedback loop. Four genes, Period1 (Per1), Period2 (Per2), Cryptochrome1 (Cry1), and Cryptochrome2 (Cry2), regulate the negative feedback within this loop. Although these proteins have distinct roles within the core circadian mechanism, their individual functions are poorly understood. Here, we used a tetracycline trans-activator system (tTA) to examine the role of transcriptional oscillations in Cry1 and Cry2 in the persistence of circadian activity rhythms. We demonstrate that rhythmic Cry1 expression is an important regulator of circadian period. We then define a critical period from birth to postnatal day 45 (PN45) where the level of Cry1 expression is critical for setting the endogenous free running period in the adult animal. Moreover, we show that, although rhythmic Cry1 expression is important, in animals with disrupted circadian rhythms overexpression of Cry1 is sufficient to restore normal behavioral periodicity. These findings provide new insights into the roles of the Cryptochrome proteins in circadian rhythmicity and further our understanding of the mammalian circadian clock.

Keywords: circadian rhythms; cryptochrome; development; gene expression; period length

DOI: https://doi.org/10.3389/fnins.2023.1166137

Cell. 2023 Jun 20. pii: S0092-8674(23)00599-8. [Epub ahead of print]

Circadian clocks are modulated by compartmentalized oscillating translation.

Terrestrial organisms developed circadian rhythms for adaptation to Earth's quasi-24-h rotation. Achieving precise rhythms requires diurnal oscillation of fundamental biological processes, such as rhythmic shifts in the cellular translational landscape; however, regulatory mechanisms underlying rhythmic translation remain elusive. Here, we identified mammalian ATXN2 and ATXN2L as cooperating master regulators of rhythmic translation, through oscillating phase separation in the suprachiasmatic nucleus along circadian cycles. The spatiotemporal oscillating condensates facilitate sequential initiation of multiple cycling processes, from mRNA processing to protein translation, for selective genes including core clock genes. Depleting ATXN2 or 2L induces opposite alterations to the circadian period, whereas the absence of both disrupts translational activation cycles and weakens circadian rhythmicity in mice. Such cellular defect can be rescued by wild type, but not phase-separation-defective ATXN2. Together, we revealed that oscillating translation is regulated by spatiotemporal condensation of two master regulators to achieve precise circadian rhythm in mammals.

Keywords: ATXN2; ATXN2L; circadian rhythm; clock genes; membrane-less organelle; neurodegeneration; phase separation; rhythmic translation; suprachiasmatic nucleus; translational regulation

DOI: https://doi.org/10.1016/j.cell.2023.05.045