Uncovering roles of circadian rhythms in the gastrointestinal system using organoids
  • Christian Hong Ph.D
  • SLS Colloquia / Nov 28th 04:00pm / bldg.110 room N104
Circadian rhythms regulate diverse aspects of gastrointestinal physiology ranging from the composition of microbiota to bowel movements. However, development of the intestinal circadian clock and detailed molecular mechanisms regulating circadian physiology of the intestine remain largely unknown. The lack of appropriate human model systems that enable organ- and/or disease-specific interrogation of clock functions is a major obstacle hindering advancements of translational applications using chronotherapy. In this report, we show that both pluripotent stem cell- and patient-derived human intestinal enteroids (HIEs) possess robust circadian rhythms, and demonstrate circadian phase-dependent necrotic cell death responses to Clostridium difficile toxin B (TcdB). Intriguingly, mouse and human enteroids demonstrate anti-phasic necrotic cell death responses. RNA-Seq data show that a large number of genes are rhythmically expressed in both mouse and human enteroids, and to our surprise, we observe species-dependent phases of specific genes including canonical clock genes. Our findings uncover robust functions of circadian rhythms regulating a large number of clock controlled genes (CCGs) in both mouse and human enteroids that determine organism-specific circadian phase-dependent necrotic cell death responses.