bims-ciryme 2020-05-31 papers

Elife. 2020 May 27. pii: e54186. [Epub ahead of print]9

Epigenetic inheritance of circadian period in clonal cells.

Yan Li, Yongli Shan, Gokhul Krishna Kilaru, Stefano Berto, Guang-Zhong Wang, Kimberly H Cox, Seung-Hee Yoo, Shuzhang Yang, Genevieve Konopka, Joseph S Takahashi.

Circadian oscillations are generated via transcriptional-translational negative feedback loops. However, individual cells from fibroblast cell lines have heterogeneous rhythms, oscillating independently and with different period lengths. Here we showed that heterogeneity in circadian period is heritable and used a multi-omics approach to investigate underlying mechanisms. By examining large-scale phenotype-associated gene expression profiles in hundreds of mouse clonal cell lines, we identified and validated multiple novel candidate genes involved in circadian period determination in the absence of significant genomic variants. We also discovered differentially co-expressed gene networks that were functionally associated with period length. We further demonstrated that global differential DNA methylation bidirectionally regulated these same gene networks. Interestingly, we found that depletion of DNMT1 and DNMT3A had opposite effects on circadian period, suggesting non-redundant roles in circadian gene regulation. Together, our findings identify novel gene candidates involved in periodicity, and reveal DNA methylation as an important regulator of circadian periodicity.

Keywords: mouse; neuroscience

DOI: https://doi.org/10.7554/eLife.54186

Obesity (Silver Spring). 2020 May 28.

Ticking for Metabolic Health: The Skeletal-Muscle Clocks.

Miguel A Gutierrez-Monreal, Jan-Frieder Harmsen, Patrick Schrauwen, Karyn A Esser.

To be prepared for alternating metabolic demands occurring over the 24-hour day, the body preserves information on time in skeletal muscle, and in all cells, through a circadian-clock mechanism. Skeletal muscle can be considered the largest collection of peripheral clocks in the body, with a major contribution to whole-body energy metabolism. Comparison of circadian-clock gene expression between skeletal muscle of nocturnal rodents and diurnal humans reveals very common patterns based on rest/active cycles rather than light/dark cycles. Rodent studies in which the circadian clock is disrupted in skeletal muscle demonstrate impaired glucose handling and insulin resistance. Experimental circadian misalignment in humans modifies the skeletal-muscle clocks and leads to disturbed energy metabolism and insulin resistance. Preclinical studies have revealed that timing of exercise over the day can influence the beneficial effects of exercise on skeletal-muscle metabolism, and studies suggest similar applicability in humans. Current strategies to improve metabolic health (e.g., exercise) should be reinvestigated in their capability to modify the skeletal-muscle clocks by taking timing of the intervention into account.

DOI: https://doi.org/10.1002/oby.22826

Endocrinology. 2020 May 26. pii: bqaa084. [Epub ahead of print]

Pro-inflammatory Cytokine Interleukin 1β Disrupts β cell Circadian Clock Function and Regulation of Insulin Secretion.

Naureen Javeed, Matthew R Brown, Kuntol Rakshit, Tracy Her, Satish K Sen, Aleksey V Matveyenko.

Intrinsic β cell circadian clocks are important regulators of insulin secretion and overall glucose homeostasis. Whether the circadian clock in β cells is perturbed following exposure to pro-diabetogenic stressors such as pro-inflammatory cytokines, and whether these perturbations are featured during the development of diabetes, remains unknown. To address this, we examined the effects of cytokine-mediated inflammation common to the pathophysiology of diabetes, on the physiological and molecular regulation of the β cell circadian clock. Specifically, we provide evidence that the key diabetogenic cytokine IL-1β disrupts functionality of the β cell circadian clock and impairs circadian regulation of glucose-stimulated insulin secretion. The deleterious effects of IL-1β on the circadian clock were attributed to impaired expression of key circadian transcription factor Bmal1, and its regulator, the NAD-dependent deacetylase, Sirtuin 1 (Sirt1). Moreover, we also identified that Type 2 diabetes in humans is associated with reduced immunoreactivity of β cell BMAL1 and SIRT1, suggestive of a potential causative link between islet inflammation, circadian clock disruption, and β cell failure. These data suggest that the circadian clock in β cells is perturbed following exposure to pro-inflammatory stressors and highlights the potential for therapeutic targeting of the circadian system for treatment β cell failure in diabetes.

Keywords: circadian clock; cytokines; diabetes; inflammation; β-cell

DOI: https://doi.org/10.1210/endocr/bqaa084

Front Neurol. 2020 ;11 327

Epilepsy and Its Interaction With Sleep and Circadian Rhythm.

Bo Jin, Thandar Aung, Yu Geng, Shuang Wang.

Growing evidence shows the bidirectional interactions between sleep, circadian rhythm, and epilepsy. Comprehending how these interact with each other may help to advance our understanding of the pathophysiology of epilepsy and develop new treatment strategies to improve seizure control by reducing the medication side effects and the risks associated with seizures. In this review, we present the overview of different temporal patterns of interictal epileptiform discharges and epileptic seizures over a period of 24 consecutive hours. Furthermore, we discuss the underlying mechanism of the core-clock gene in periodic seizure occurrences. Finally, we outline the role of circadian patterns of seizures on seizure forecasting models and its implication for chronotherapy in epilepsy.

Keywords: chronotherapy; circadian rhythms; epilepsy; seizure forecasting; sleep

DOI: https://doi.org/10.3389/fneur.2020.00327