{"doi":"10.1016/j.jcmgh.2023.06.011","title":"The Untapped Potential of Circadian Timing as a Variable for Discoveries and Reproducibility","abstract":"Identifying the molecular changes between healthy and diseased states is crucial for understanding disease mechanisms. de Assis et al1de Assis L.V.M. Demir M. Oster H. Non-alcoholic steatohepatitis disrupts diurnal liver transcriptome rhythms in mice.Cell Mol Gastroenterol Hepatol. 2023; Google Scholar highlighted 2 overlooked variables with significant impacts on research outcomes: sample collection timing and the influence of the disease state on tissue circadian rhythms. Considering these factors can enhance our understanding of diseases, improve biomarker identification, prognosis, and address reproducibility issues. Circadian or ∼24-hour rhythms are fundamental aspects of behavior, physiology, and metabolism in humans and animals. These rhythms are governed by cell autonomous circadian clocks, consisting of a few transcriptional regulators found in almost all nucleated cells. These clock components interact with cell-specific factors to generate circadian patterns in the mRNA levels of hundreds to thousands of target genes, known as “output genes,” across various organs, including the liver.2Panda S. Hogenesch J.B. Kay S.A. Circadian rhythms from flies to human.Nature. 2002; 417: 329-335Crossref PubMed Scopus (778) Google Scholar Together, these clock components and output genes form the circadian system. However, the circadian system is also responsive to metabolic, endocrine, and physiological factors, resulting in changes in at least 3 key aspects of circadian gene expression. First, the peak level of a transcript may not rise or fall to extreme levels, thereby dampening its rhythmicity or rendering it non-rhythmic. Conversely, a transcript may gain rhythmic expression in response to a chronic disturbance. Second, both the peak and trough expression levels, or the mesor (average level), may increase or decrease. Third, the peak expression of a transcript may be delayed or advanced. It is also conceivable that various combinations of these primary changes can occur in rhythmic expression. The plasticity of the circadian system has several implications for health and disease. Epidemiological studies and controlled laboratory experiments have demonstrated that chronic disruption of the circadian clock, either through genetic factors or non-genetic factors such as shift work, can contribute to various chronic diseases affecting almost every organ.3Sulli G. Manoogian E.N.C. Taub P.R. et al.Training the circadian clock, clocking the drugs, and drugging the clock to prevent, manage, and treat chronic diseases.Trends Pharmacol Sci. 2018; 39: 812-827Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar Furthermore, many disease-causing agents, including obesogenic diets, have been found to disrupt the circadian system, making circadian disruption itself an important etiology of disease. Additionally, changes in metabolism, physiology, and endocrine factors within a diseased organ can disrupt the circadian system locally or even in distant tissues,4Masri S. Papagiannakopoulos T. Kinouchi K. et al.Lung adenocarcinoma distally rewires hepatic circadian homeostasis.Cell. 2016; 165: 896-909Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar thereby exacerbating the disease. Consequently, the state of the circadian system becomes an integral part of the molecular milieu of the disease. In their study, de Assis et al1de Assis L.V.M. Demir M. Oster H. Non-alcoholic steatohepatitis disrupts diurnal liver transcriptome rhythms in mice.Cell Mol Gastroenterol Hepatol. 2023; Google Scholar systematically addressed this issue in a mouse model of nonalcoholic steatohepatitis (NASH). The authors re-analyzed transcriptome changes in a mouse model of NASH reported by 3 independent groups,5Lee S.M. Pusec C.M. Norris G.H. et al.Hepatocyte-specific loss of PPARgamma protects mice from NASH and increases the therapeutic effects of rosiglitazone in the liver.Cell Mol Gastroenterol Hepatol. 2021; 11: 1291-1311Abstract Ful","journal":"Cellular and Molecular Gastroenterology and Hepatology","year":2023,"id":409313,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.938,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":407408,"name":"Satchidananda Panda","orcid":"0000-0002-7855-0091","position":0,"is_corresponding":true}],"reference_count":7,"raw_metadata":null,"created_at":"2026-07-19T01:21:27.199694Z","pmid":"37423258","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}