bims-ciryme 2022-04-17 papers

Cell Rep. 2022 Apr 12. pii: S2211-1247(22)00426-0. [Epub ahead of print]39(2): 110674

The hepatocyte insulin receptor is required to program the liver clock and rhythmic gene expression.

Liver physiology is circadian and sensitive to feeding and insulin. Food intake regulates insulin secretion and is a dominant signal for the liver clock. However, how much insulin contributes to the effect of feeding on the liver clock and rhythmic gene expression remains to be investigated. Insulin action partly depends on changes in insulin receptor (IR)-dependent gene expression. Here, we use hepatocyte-restricted gene deletion of IR to evaluate its role in the regulation and oscillation of gene expression as well as in the programming of the circadian clock in the adult mouse liver. We find that, in the absence of IR, the rhythmicity of core-clock gene expression is altered in response to day-restricted feeding. This change in core-clock gene expression is associated with defective reprogramming of liver gene expression. Our data show that an intact hepatocyte insulin receptor is required to program the liver clock and associated rhythmic gene expression.

Keywords: CLOCK; CP: Metabolism; CP: Molecular biology; circadian; hepatocyte; insulin; insulin receptor; liver; metabolism

DOI: https://doi.org/10.1016/j.celrep.2022.110674

EMBO Rep. 2022 Apr 12. e52412

Nutrition, metabolism, and epigenetics: pathways of circadian reprogramming.

Tomoki Sato, Paolo Sassone-Corsi.

Food intake profoundly affects systemic physiology. A large body of evidence has indicated a link between food intake and circadian rhythms, and ~24-h cycles are deemed essential for adapting internal homeostasis to the external environment. Circadian rhythms are controlled by the biological clock, a molecular system remarkably conserved throughout evolution. The circadian clock controls the cyclic expression of numerous genes, a regulatory program common to all mammalian cells, which may lead to various metabolic and physiological disturbances if hindered. Although the circadian clock regulates multiple metabolic pathways, metabolic states also provide feedback on the molecular clock. Therefore, a remarkable feature is reprogramming by nutritional challenges, such as a high-fat diet, fasting, ketogenic diet, and caloric restriction. In addition, various factors such as energy balance, histone modifications, and nuclear receptor activity are involved in the remodeling of the clock. Herein, we review the interaction of dietary components with the circadian system and illustrate the relationships linking the molecular clock to metabolism and critical roles in the remodeling process.

Keywords: circadian clock; energy metabolism; epigenetics; nutrition

DOI: https://doi.org/10.15252/embr.202152412

Phys Rev E. 2022 Mar;105(3-1): 034411

Promoter methylation in a mixed feedback loop circadian clock model.

Turner Silverthorne, Edward Saehong Oh, Adam R Stinchcombe.

We investigate how epigenetic modifications to clock gene promoters affect transcriptomic activity in the circadian clock. Motivated by experimental observations that link DNA methylation with the behavior of the clock, we introduce and analyze an extension of the mixed feedback loop (MFL) model of François and Hakim. We extend the original model to include an additional methylated promoter state and allow for reversible protein sequestration, an important feature for circadian applications. First, working with the general form of the MFL model, we find that the qualitative behavior of the model is dictated by the promoter state with the highest transcription rate. We then build on the work of Kim and Forger, who analyzed the stability of the mammalian circadian clock by using a reduced form of the MFL model. We present a rigorous procedure for translating between the MFL model and the reduction of Kim and Forger. We then propose a model reduction more appropriate for the study of oscillatory promoter states, making use of a fully coupled quasi-steady-state approximation rather than the standard partially uncoupled quasi-steady-state approach. Working with the novel reduced form of the model, we find substantial differences in the transcription function and show that, although methylation contributes to period control, excessive methylation can abolish rhythmicity. Altogether our results show that even in a minimal clock model, DNA methylation has a nontrivial influence on the system's ability to oscillate.

DOI: https://doi.org/10.1103/PhysRevE.105.034411

Cell Rep. 2022 Apr 12. pii: S2211-1247(22)00387-4. [Epub ahead of print]39(2): 110635

CLOCK regulates Drp1 mRNA stability and mitochondrial homeostasis by interacting with PUF60.

Lirong Xu, Jiaxin Lin, Yutong Liu, Bingxuan Hua, Qianyun Cheng, Changpo Lin, Zuoqin Yan, Yaping Wang, Ning Sun, Ruizhe Qian, Chao Lu.

Circadian genes such as Clock, Bmal1, Cryptochrome1/2, and Period1/2/3 constitute the precise circadian system. ClockΔ19 is a commonly used mouse model harboring a circadian clock gene mutation, which lacks the EXON-19-encoded 51 amino acids. Previous reports have shown that ClockΔ19 mice have severe metabolic abnormalities. Here, we report that the mitochondria of ClockΔ19 mice exhibit excessive fission and dysfunction. We also demonstrate that CLOCK binds to the RNA-binding protein PUF60 through its EXON 19. Further, we find that PUF60 directly maintains mitochondrial homeostasis through regulating Drp1 mRNA stability, while the association with CLOCK can competitively inhibit this function. In ClockΔ19 mice, CLOCKΔ19 releases PUF60, leading to enhanced Drp1 mRNA stability and persistent mitochondrial fission. Our results reveal a direct post-transcriptional role of CLOCK in regulating mitochondrial homeostasis via Drp1 mRNA stability and that the loss of EXON 19 of CLOCK in ClockΔ19 mice leads to severe mitochondrial homeostasis disorders.

Keywords: CP: Metabolism; CP: Molecular biology; Clock; Drp1; PUF60; mRNA stability; mitochondrial fission

DOI: https://doi.org/10.1016/j.celrep.2022.110635