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Effect of 8-weeks of chronic jet lag lighting (CJL) on gene expression in the livers of Eu-MYC mice

ABSTRACT: Background: Disruption of natural diurnal light cycles, such as that experienced by shift workers, is linked to enhanced cancer incidence. Several mouse models of cancer have been shown to develop more severe disease when exposed to irregular light/dark cycles, further supporting the connection between circadian disruption and increased cancer risk. Cryptochrome 2 (CRY2), a repressive component of the molecular circadian clock, facilitates the turnover of the oncoprotein c-MYC, one mechanism that may link the molecular clock to tumorigenesis. In Eμ-MYC mice, which express transgenic c-MYC in B cells and develop aggressive lymphomas and leukemia, global Cry2 deletion reduces overall survival and enhances tumor formation. Lighting conditions that mimic the disruption experienced by shift workers dampen Cry2 transcripts in peripheral tissues of C57BL/6J mice. Although it is much milder than homozygous deletion of Cry2, we hypothesized that reduced Cry2 rhythmicity could alter MYC protein accumulation and contribute to enhanced cancer risk caused by circadian disruption. We decided to test this hypothesis in the context of MYC-driven lymphoma. Methods: We housed Eμ-MYC mice in light-tight boxes set to either the control (continuous cycles of 12-hours of light followed by 12-hours of dark, LD12:12) or chronic jetlag (eight-hour light phase advances every two to three days, CJL) lighting conditions and assessed the impact of disrupted light cycles on overall survival and tumor formation in Eμ-MYC mice. Results: Environmental disruption of circadian rhythms did not alter tumor location, tumor growth, or overall survival in female or male Eμ-MYC mice on the c57BL6 genetic background. Conclusions: The dampened transcriptional rhythms of Cry2 caused by exposure to disruption of circadian light exposures is very different from the complete loss of Cry2 expression caused by genetic deletion. The lack of any phenotype caused by altered circadian gene expression patterns in contrast to the enhanced tumorigenesis caused by homozygous deletion of Cry2 suggests that the dosage of CRY2 may impact this model. Importantly, these findings indicate that the well-documented increase in cancer risk associated with circadian disruption arises from one or more mechanisms that are not recapitulated in this mouse model, and may be different in distinct tumor types.

ORGANISM(S): Mus musculus

PROVIDER: GSE242159 | GEO | 2024/08/29

REPOSITORIES: GEO

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Project description:We utilized the Nematostella vectensis to quantify gene expression differences and loss during light:dark cycling and immediately after light cue removal through comparisons of 136 transcriptomes Organismal responses to light:dark cycles can result from two general processes: (i) direct response to light or (ii) a free-running rhythm (i.e., a circadian clock). Previous research in cnidarians has shown that candidate circadian clock genes have rhythmic expression in the presence of diel lighting, but these oscillations appear to be lost quickly after removal of the light cue. Here, we measure whole-organism gene expression changes in 136 transcriptomes of the sea anemone Nematostella vectensis, entrained to a light:dark environment and immediately following light cue removal to distinguish two broadly defined responses in cnidarians: light entrainment and circadian regulation. Direct light exposure resulted in significant differences in expression for hundreds of genes, including more than 200 genes with rhythmic, 24-hour periodicity. Removal of the lighting cue resulted in the loss of significant expression for 80% of these genes after one day, including most of the hypothesized cnidarian circadian genes. Further, 70% of these candidate genes were phase shifted. Most surprisingly, thousands of genes, some of which are involved in oxidative stress, DNA damage response, and chromatin modification, had significant differences in expression in the 24 hours following light removal, suggesting that loss of the entraining cue may induce a cellular stress response. Together, our findings suggest that a majority of genes with significant differences in expression for anemones cultured under diel lighting are largely driven by the primary photoresponse rather than a circadian clock when measured at the whole animal level. These results provide context for the evolution of cnidarian circadian biology and help to disassociate two commonly confounded factors driving oscillating phenotypes.

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Effect of 8-weeks of chronic jet lag lighting (CJL) on gene expression in the livers of Eu-MYC mice

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