Basic research and opportunities for translational advancement in the field of mammalian ∼12-hour ultradian chronobiology

Abstract

Repetitive variations, such as oscillation, are ubiquitous in biology. In this mini review, we present a general summary of the ∼24 h circadian clock and provide a fundamental overview of another biological timekeeper that maintains ∼12 h oscillations. This ∼12 h oscillator is proposed to function independently of the circadian clock to regulate ultradian biological rhythms relevant to both protein homeostasis and liver health. Recent studies exploring these ∼12 h rhythms in humans are discussed, followed by our proposal that mammary gland physiology represents a promising area for further research. We conclude by highlighting potential translational applications in ∼12 h ultradian chronobiology.

Keywords: NAFLD/MAFLD; XBP1s; circadian rhythm; nuclear speckles; proteostasis; ultradian rhythm; unfolded protein response.

FIGURE 1

Ultradian biological rhythms of nuclear speckle liquid-liquid phase separation dynamics and proteostasis. (A) Nuclear speckle morphology (indicated by SC35 signal) in mouse liver at different timepoints. Normal nuclear speckle morphologies alternate between punctate (CT2 and CT14) and diffuse (CT8 and CT20). Panel taken from Figure 1A of Dion et al., 2022, ^© The Authors, some rights reserved; exclusive licensee AAAS. Distributed under a Creative Commons Attribution License 4.0 (CC BY) https://creativecommons.org/licenses/by/4.0/. (B) Characteristics associated with different nuclear speckle morphologies (nuclear speckle (NS), liquid-liquid phase separation (LLPS)). (C) Our lake analogy shows full and drying lakes representing normally occurring nuclear speckle morphologies and green shrubs which represent chromatin. The changes in the water’s distance from the green shrubs could be understood as how nuclear speckles' proximity to chromatin normally changes over time. Image created with BioRender.com.

FIGURE 2

Post hoc analysis of the human milk fat globule temporal transcriptome. Data from the published study are available through the NCBI Gene Expression Omnibus, identifier GSE12669 (Maningat et al., 2009). (A) Total cycling genes with p values less than 0.05 for corresponding periods as determined with RAIN (Thaben and Westermark, 2014). (B) Temporal expression profiles of individual genes previously shown to have ultradian rhythms (Zhu et al., 2017; Pan et al., 2020).