About

John B. Hogenesch, Ph.D., is an Adjunct Professor of Systems Pharmacology and Translational Therapeutics at the Perelman School of Medicine at the University of Pennsylvania. He is also a member of the Perinatal Institute and serves as the Director of the Center for Circadian Medicine at Cincinnati Children's Hospital Medical Center, where he is the Director of Research in the Division of Human Genetics. His laboratory researches the mammalian circadian clock, focusing on how it regulates daily rhythms of physiology and behavior in mammals. Using systems biology approaches, genomic, and computational tools, his team aims to identify new clock genes and understand how the clock keeps time, with the goal of translating these findings into practical applications for human health and disease. His work seeks to gain a comprehensive understanding of the circadian clock and its impact on physiology and behavior to improve human health and wellbeing.

Research topics

• Medicine
• Internal medicine
• Endocrinology
• Biology
• Intensive care medicine
• Biochemistry
• Oncology
• Physiology
• Cancer research
• Cardiology
• Cell biology

Selected publications

• Clock Regulation of Metabolites Reveals Coupling between Transcription and Metabolism

  UNC Libraries · 2026-01-14

  articleOpen access
  PublisherDOI

• Mutations of the circadian clock genes Cry, Per, or Bmal1 have different effects on the transcribed and nontranscribed strands of cycling genes

  UNC Libraries · 2026-01-14

  articleOpen accessSenior author

  One important goal of circadian medicine is to apply time-of-day dosing to improve the efficacy of chemotherapy. However, limited knowledge of how the circadian clock regulates DNA repair presents a challenge to mechanism-based clinical application. We studied time-series genome-wide nucleotide excision repair in liver and kidney of wild type and three different clock mutant genotypes (<em>Cry1</em>^-/-<em>Cry2</em>^-/-, <em>Per1</em>^-/-<em>Per2</em>^-/-, and <em>Bmal1</em>^-/-). Rhythmic repair on the nontranscribed strand was lost in all three clock mutants. Conversely, rhythmic repair of hundreds of genes on the transcribed strand (TSs) persisted in the livers of <em>Cry1</em>^-/-<em>Cry2</em>^-/- and <em>Per1</em>^-/-<em>Per2</em>^-/- mice. We identified a tissue-specific, promoter element-driven repair mode on TSs of collagen and angiogenesis genes in the absence of clock activators or repressors. Furthermore, repair on TSs of thousands of genes was altered when the circadian clock is disrupted. These data contribute to a better understanding of the regulatory role of the circadian clock on nucleotide excision repair in mammals and may be invaluable toward the design of time-aware platinum-based interventions in cancer.

  PublisherDOI

• Short-term 24h dietary recalls from observational studies cannot support claims on mortality

  Diabetes & Metabolic Syndrome Clinical Research & Reviews · 2025-10-01 · 1 citations

  articleOpen access
  PublisherOA PDFDOI

• Mutations of the circadian clock genes <i>Cry</i> , <i>Per,</i> or <i>Bmal1</i> have different effects on the transcribed and nontranscribed strands of cycling genes

  Proceedings of the National Academy of Sciences · 2024-02-15 · 10 citations

  articleOpen accessSenior authorCorresponding

  One important goal of circadian medicine is to apply time-of-day dosing to improve the efficacy of chemotherapy. However, limited knowledge of how the circadian clock regulates DNA repair presents a challenge to mechanism-based clinical application. We studied time-series genome-wide nucleotide excision repair in liver and kidney of wild type and three different clock mutant genotypes ( Cry1 −/− Cry2 −/− , Per1 −/− Per2 −/− , and Bmal1 −/− ). Rhythmic repair on the nontranscribed strand was lost in all three clock mutants. Conversely, rhythmic repair of hundreds of genes on the transcribed strand (TSs) persisted in the livers of Cry1 −/− Cry2 −/− and Per1 −/− Per2 −/− mice. We identified a tissue-specific, promoter element-driven repair mode on TSs of collagen and angiogenesis genes in the absence of clock activators or repressors. Furthermore, repair on TSs of thousands of genes was altered when the circadian clock is disrupted. These data contribute to a better understanding of the regulatory role of the circadian clock on nucleotide excision repair in mammals and may be invaluable toward the design of time-aware platinum-based interventions in cancer.

  PublisherOA PDFDOI

• Circadian disruption, clock genes, and metabolic health

  Journal of Clinical Investigation · 2024-07-14 · 156 citations

  reviewOpen access

  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.

  PublisherOA PDFDOI

• Tumor circadian clock strength influences metastatic potential and predicts patient prognosis in luminal A breast cancer

  Proceedings of the National Academy of Sciences · 2024 · 48 citations

  • Biology
  • Internal medicine
  • Cancer research

  Studies in shift workers and model organisms link circadian disruption to breast cancer. However, molecular circadian rhythms in noncancerous and cancerous human breast tissues and their clinical relevance are largely unknown. We reconstructed rhythms informatically, integrating locally collected, time-stamped biopsies with public datasets. For noncancerous breast tissue, inflammatory, epithelial-mesenchymal transition (EMT), and estrogen responsiveness pathways show circadian modulation. Among tumors, clock correlation analysis demonstrates subtype-specific changes in circadian organization. Luminal A organoids and informatic ordering of luminal A samples exhibit continued, albeit dampened and reprogrammed rhythms. However, CYCLOPS magnitude, a measure of global rhythm strength, varied widely among luminal A samples. Cycling of EMT pathway genes was markedly increased in high-magnitude luminal A tumors. Surprisingly, patients with high-magnitude tumors had reduced 5-y survival. Correspondingly, 3D luminal A cultures show reduced invasion following molecular clock disruption. This study links subtype-specific circadian disruption in breast cancer to EMT, metastatic potential, and prognosis.

  PublisherOA PDFDOI

• Widespread annual rhythms in pediatric emergencies

  medRxiv · 2024-12-20

  preprintOpen access

  Abstract Assessments of emergency department (ED) utilization for specific medical conditions reveal distinct annual rhythms, providing valuable insights into risk factors and optimal clinical staffing. However, focusing on a single condition in isolation can lack essential context. Such rhythms may (i) depend on co-occurrence with other conditions, (ii) be obscured by systemic factors that influence all conditions similarly, or (iii) offer limited clinical utility without understanding their rhythmic effect sizes relative to other emergencies. Using a unified framework for analysis, we studied the annual variation in incidences of all chief complaints (CCs) from 1.5 million admissions to our pediatric ED and urgent care centers from 2010 to 2021, enabling comparison of seasonality, effect sizes, and interactions across all types of emergencies. Most CCs (∼80%) had annual rhythms, with a range of phases. Specific patterns, such as spring and fall peaks in neurologic-, injury-, and psychiatric-related CCs, have immediate significance. For example, psychiatric emergencies, which the American Academy of Pediatrics has designated a national crisis, were among the largest rhythmic effect sizes of all CCs. Further evaluation integrating ICD-10 diagnoses identified patient subtypes for psychiatric and other CCs, suggesting distinct annual influences. Using counterpart data from across Brazil, we identified marked global differences in annual patterns of ED utilization, including psychiatric emergencies. Lastly, we identified CCs with large weekday effects, impacting care and staffing needs, especially when combined with annual rhythms.

  PublisherOA PDFDOI

• Clinical and functional studies of MTOR variants in Smith-Kingsmore syndrome reveal deficits of circadian rhythm and sleep-wake behavior

  Human Genetics and Genomics Advances · 2024-07-18 · 3 citations

  articleOpen access

  Heterozygous de novo or inherited gain-of-function mutations in the MTOR gene cause Smith-Kingsmore syndrome (SKS). SKS is a rare autosomal dominant condition, and individuals with SKS display macrocephaly/megalencephaly, developmental delay, intellectual disability, and seizures. A few dozen individuals are reported in the literature. Here, we report a cohort of 28 individuals with SKS that represent nine MTOR pathogenic variants. We conducted a detailed natural history study and found pathophysiological deficits among individuals with SKS in addition to the common neurodevelopmental symptoms. These symptoms include sleep-wake disturbance, hyperphagia, and hyperactivity, indicative of homeostatic imbalance. To characterize these variants, we developed cell models and characterized their functional consequences. We showed that these SKS variants display a range of mechanistic target of rapamycin (mTOR) activities and respond to the mTOR inhibitor, rapamycin, differently. For example, the R1480_C1483del variant we identified here and the previously known C1483F are more active than wild-type controls and less responsive to rapamycin. Further, we showed that SKS mutations dampened circadian rhythms and low-dose rapamycin improved the rhythm amplitude, suggesting that optimal mTOR activity is required for normal circadian function. As SKS is caused by gain-of-function mutations in MTOR, rapamycin was used to treat several patients. While higher doses of rapamycin caused delayed sleep-wake phase disorder in a subset of patients, optimized lower doses improved sleep. Our study expands the clinical and molecular spectrum of SKS and supports further studies for mechanism-guided treatment options to improve sleep-wake behavior and overall health.

  PublisherOA PDFDOI

• Trajectory of Sleep, Depression, and Quality of Life in Pediatric HSCT Recipients

  Transplantation and Cellular Therapy · 2024-04-03 · 3 citations

  article
  PublisherDOI

• Circadian Medicine Education: The Time Has Arrived

  Journal of Biological Rhythms · 2024-11-14 · 3 citations

  editorialOpen accessSenior author
  PublisherOA PDFDOI

Recent grants

• NIH Grant R01HL097800

  NIH · $1.5M · 2013

• Molecular, cellular and physiological mechanisms of the mammalian circadian clock

  NIH · $484k · 2007–2012

• NIH Grant U54HL117798

  NIH · $36.7M · 2018

• Molecular, cellular and physiological mechanisms of the mammalian circadian clock

  NIH · $7.0M · 2007–2024

• Integrated Informatic and Experimental Evaluations of Cancer Chronotherapy

  NIH · $3.0M · 2019–2025

Frequent coauthors

• David F. Smith

  81 shared

• Gang Wu

  Cincinnati Children's Hospital Medical Center

  76 shared

• Lauren J. Francey

  Beth Israel Deaconess Medical Center

  71 shared

• Ron C. Anafi

  University of Pennsylvania

  57 shared

• Julie E. Baggs

  52 shared

• Marc D. Ruben

  Cincinnati Children's Hospital Medical Center

  44 shared

• Satchidananda Panda

  Salk Institute for Biological Studies

  42 shared

• Anand Venkataraman

  University of British Columbia

  36 shared