Dataset Information

Pathway-level analysis of genome-wide circadian dynamics in diverse tissues in rat and mouse.

ABSTRACT: A computational framework is developed to enable the characterization of genome-wide, multi-tissue circadian dynamics at the level of "functional groupings of genes" defined in the context of signaling, cellular/genetic processing and metabolic pathways in rat and mouse. Our aim is to identify how individual genes come together to generate orchestrated rhythmic patterns and how these may vary within and across tissues. We focus our analysis on four tissues (adipose, liver, lung, and muscle). A genome-wide pathway-centric analysis enables us to develop a comprehensive picture on how the observed circadian variation at the individual gene level, orchestrates functional responses at the pathway level. Such pathway-based "meta-data" analysis enables the rational integration and comparison across platforms and/or experimental designs evaluating emergent dynamics, as opposed to comparisons of individual elements. One of our key findings is that when considering the dynamics at the pathway level, a complex behavior emerges. Our work proposes that tissues tend to coordinate gene's circadian expression in a way that optimizes tissue-specific pathway activity, depending of each tissue's broader role in homeostasis.

SUBMITTER: Acevedo A

PROVIDER: S-EPMC8844946 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Pathway-level analysis of genome-wide circadian dynamics in diverse tissues in rat and mouse.

Acevedo Alison A Mavroudis Panteleimon D PD DuBois Debra D Almon Richard R RR Jusko William J WJ Androulakis Ioannis P IP

Journal of pharmacokinetics and pharmacodynamics 20210325 3

A computational framework is developed to enable the characterization of genome-wide, multi-tissue circadian dynamics at the level of "functional groupings of genes" defined in the context of signaling, cellular/genetic processing and metabolic pathways in rat and mouse. Our aim is to identify how individual genes come together to generate orchestrated rhythmic patterns and how these may vary within and across tissues. We focus our analysis on four tissues (adipose, liver, lung, and muscle). A g ...[more]

PMID: 33768484

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Project description:BackgroundDysfunction of the circadian clock and single polymorphisms of some circadian genes have been linked to cancer susceptibility, although data are scarce and findings inconsistent. We aimed to investigate the association between circadian pathway genetic variation and risk of developing common cancers based on the findings of genome-wide association studies (GWASs).MethodsSingle nucleotide polymorphisms (SNPs) of 17 circadian genes reported by three GWAS meta-analyses dedicated to breast (Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Consortium; cases, n = 15,748; controls, n = 18,084), prostate (Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) Consortium; cases, n = 14,160; controls, n = 12,724) and lung carcinoma (Transdisciplinary Research In Cancer of the Lung (TRICL) Consortium; cases, n = 12,160; controls, n = 16,838) in patients of European ancestry were utilized to perform pathway analysis by means of the adaptive rank truncated product (ARTP) method. Data were also available for the following subgroups: estrogen receptor negative breast cancer, aggressive prostate cancer, squamous lung carcinoma and lung adenocarcinoma.ResultsWe found a highly significant statistical association between circadian pathway genetic variation and the risk of breast (pathway P value = 1.9 × 10-6; top gene RORA, gene P value = 0.0003), prostate (pathway P value = 4.1 × 10-6; top gene ARNTL, gene P value = 0.0002) and lung cancer (pathway P value = 6.9 × 10-7; top gene RORA, gene P value = 2.0 × 10-6), as well as all their subgroups. Out of 17 genes investigated, 15 were found to be significantly associated with the risk of cancer: four genes were shared by all three malignancies (ARNTL, CLOCK, RORA and RORB), two by breast and lung cancer (CRY1 and CRY2) and three by prostate and lung cancer (NPAS2, NR1D1 and PER3), whereas four genes were specific for lung cancer (ARNTL2, CSNK1E, NR1D2 and PER2) and two for breast cancer (PER1, RORC).ConclusionsOur findings, based on the largest series ever utilized for ARTP-based gene and pathway analysis, support the hypothesis that circadian pathway genetic variation is involved in cancer predisposition.

Dataset Information

Pathway-level analysis of genome-wide circadian dynamics in diverse tissues in rat and mouse.

Publications

Pathway-level analysis of genome-wide circadian dynamics in diverse tissues in rat and mouse.

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