bims-ciryme 2024-07-21 papers

Issue of 2024‒07‒21
four papers selected by
Gabriela Da Silva Xavier, University of Birmingham

Sci Rep. 2024 Jul 14. 14(1): 16238

Quantification of circadian rhythms in mammalian lung tissue snapshot data.

Saskia Grabe, Bharath Ananthasubramaniam, Hanspeter Herzel.

Healthy mammalian cells have a circadian clock, a gene regulatory network that allows them to schedule their physiological processes to optimal times of the day. When healthy cells turn into cancer cells, the circadian clock often becomes cancer specifically disturbed, so there is an interest in the extraction of circadian features from gene expression data of cancer. This is challenging, as clinical gene expression samples of cancer are snapshot-like and the circadian clock is best examined using gene expression time series. In this study, we obtained lists of intersecting circadian genes in public gene expression time series data of lung tissue of mouse and baboon. We base our circadian gene lists on correlations of gene expression levels of circadian genes, which are closely associated to the phase differences between them. Combining circadian gene expression patterns of diurnal and nocturnal species of different ages provides circadian genes that are also important in healthy and cancerous human lung tissue. We tested the quality of the representation of the circadian clock in our gene lists by PCA-based reconstructions of the circadian times of the mouse and baboon samples. Then we assigned potential circadian times to the human lung tissue samples and find an intact circadian clock in the healthy human lung tissue, but an altered, weak clock in the adjacent cancerous lung tissue.

DOI: https://doi.org/10.1038/s41598-024-66694-7

J Clin Invest. 2024 Jul 15. pii: e170998. [Epub ahead of print]134(14):

Circadian disruption, clock genes, and metabolic health.

Lauren A Schrader, Sean M Ronnekleiv-Kelly, John B Hogenesch, Christopher A Bradfield, Kristen Mc Malecki.

A growing body of research has identified circadian-rhythm disruption as a risk factor for metabolic health. However, the underlying biological basis remains complex, and complete molecular mechanisms are unknown. There is emerging evidence from animal and human research to suggest that the expression of core circadian genes, such as circadian locomotor output cycles kaput gene (CLOCK), brain and muscle ARNT-Like 1 gene (BMAL1), period (PER), and cyptochrome (CRY), and the consequent expression of hundreds of circadian output genes are integral to the regulation of cellular metabolism. These circadian mechanisms represent potential pathophysiological pathways linking circadian disruption to adverse metabolic health outcomes, including obesity, metabolic syndrome, and type 2 diabetes. Here, we aim to summarize select evidence from in vivo animal models and compare these results with epidemiologic research findings to advance understanding of existing foundational evidence and potential mechanistic links between circadian disruption and altered clock gene expression contributions to metabolic health-related pathologies. Findings have important implications for the treatment, prevention, and control of metabolic pathologies underlying leading causes of death and disability, including diabetes, cardiovascular disease, and cancer.

DOI: https://doi.org/10.1172/JCI170998

Proc Natl Acad Sci U S A. 2024 Jul 23. 121(30): e2319782121

Hypermetabolic state is associated with circadian rhythm disruption in mouse and human cancer cells.

Daniel Maxim Iascone, Xue Zhang, Patricia Brafford, Clementina Mesaros, Yogev Sela, Samuel Hofbauer, Shirley L Zhang, Sukanya Madhwal, Kieona Cook, Pavel Pivarshev, Ben Z Stanger, Stewart Anderson, Chi V Dang, Amita Sehgal.

Crosstalk between metabolism and circadian rhythms is a fundamental building block of multicellular life, and disruption of this reciprocal communication could be relevant to disease. Here, we investigated whether maintenance of circadian rhythms depends on specific metabolic pathways, particularly in the context of cancer. We found that in adult mouse fibroblasts, ATP levels were a major contributor to signal from a clock gene luciferase reporter, although not necessarily to the strength of circadian cycling. In contrast, we identified significant metabolic control of circadian function across a series of pancreatic adenocarcinoma cell lines. Metabolic profiling of congenic tumor cell clones revealed substantial diversity among these lines that we used to identify clones to generate circadian reporter lines. We observed diverse circadian profiles among these lines that varied with their metabolic phenotype: The most hypometabolic line [exhibiting low levels of oxidative phosphorylation (OxPhos) and glycolysis] had the strongest rhythms, while the most hypermetabolic line had the weakest rhythms. Pharmacological enhancement of OxPhos decreased the amplitude of circadian oscillation in a subset of tumor cell lines. Strikingly, inhibition of OxPhos enhanced circadian rhythms only in the tumor cell line in which glycolysis was also low, thereby establishing a hypometabolic state. We further analyzed metabolic and circadian phenotypes across a panel of human patient-derived melanoma cell lines and observed a significant negative association between metabolic activity and circadian cycling strength. Together, these findings suggest that metabolic heterogeneity in cancer directly contributes to circadian function and that high levels of glycolysis or OxPhos independently disrupt circadian rhythms in these cells.

Keywords: adenocarcinoma; cancer; circadian rhythms; luciferase; metabolism

DOI: https://doi.org/10.1073/pnas.2319782121

Proc Natl Acad Sci U S A. 2024 Jul 23. 121(30): e2315778121

GIGANTEA adjusts the response to shade at dusk by directly impinging on PHYTOCHROME INTERACTING FACTOR 7 function.

Carlos Martínez-Vasallo, Benjamin Cole, Jaime Pérez-Alemany, Clara I Ortiz-Ramírez, Javier Gallego-Bartolomé, Joanne Chory, Steve A Kay, Maria A Nohales.

For plants adapted to bright light, a decrease in the amount of light received can be detrimental to their growth and survival. Consequently, in response to shade from surrounding vegetation, they initiate a suite of molecular and morphological changes known as the shade avoidance response through which stems and petioles elongate in search for light. Under sunlight-night cycles, the plant's responsiveness to shade varies across the day, being maximal at dusk time. While a role for the circadian clock in this regulation has long been proposed, mechanistic understanding of how it is achieved is incomplete. Here, we show that the clock component GIGANTEA (GI) directly interacts with the transcriptional regulator PHYTOCHROME INTERACTING FACTOR 7 (PIF7), a key player in the response to shade. GI represses PIF7 transcriptional activity and the expression of its target genes in response to shade, thereby fine-tuning the magnitude of the response to limiting light conditions. We find that under light/dark cycles, this function of GI is required to adequately modulate the gating of the response to shade at dusk. Importantly, we also show that this circuit primarily operates in epidermal cells, highlighting the relevance of tissue-specific clock-output connections for the regulation of plant development in resonance with the environment.

Keywords: GIGANTEA; PIF7; circadian gating; shade avoidance; tissue specificity

DOI: https://doi.org/10.1073/pnas.2315778121