Ontogeny and function of the circadian clock in intestinal organoids

Autor(es):Mostrar menos -

Rosselot, Andrew E. ^[1] ; Park, Miri ^[1] ; Kim, Mari ^[1] ; Matsu-Ura, Toru ^[1] ; Wu, Gang ^[2] ; Flores, Danilo E. ^[2] ; Subramanian, Krithika R. ^[1] ; Lee, Suengwon ^[1] ; Sundaram, Nambirajan ^[3] ; Broda, Taylor R. ^[4] ; McCauley, Heather A. ^[4] ; Hawkins, Jennifer A. ^[3] ; Chetal, Kashish ^[5] ; Salomonis, Nathan ^[5] ; Shroyer, Noah F. ^[6] ; Helmrath, Michael A. ^{[3, 4]} ; Wells, James M. ^{[4, 7]} ; Hogenesch, John B. ^{[2, 8]} ; Moore, Sean R. ^[9] ; Hong, I, Christian

Afiliação do(s) autor(es)

^[1] I, Univ Cincinnati, Dept Pharmacol & Syst Physiol, Cincinnati, OH 45221 - USA

^[2] Cincinnati Childrens Hosp Med Ctr, Ctr Chronobiol, Dept Pediat, Div Human Genet & Immunobiol, Cincinnati, OH 45229 - USA

^[3] Cincinnati Childrens Hosp Med Ctr, Dept Pediat Surg, Cincinnati, OH 45229 - USA

^[4] I, Cincinnati Childrens Hosp Med Ctr, Ctr Stem Cell & Organoid Med, Div Dev Biol, Cincinnati, OH 45229 - USA

^[5] Cincinnati Childrens Hosp Med Ctr, Div Biomed Informat, Cincinnati, OH 45229 - USA

^[6] Baylor Coll Med, Gastroenterol & Hepatol, Houston, TX 77030 - USA

^[7] Cincinnati Childrens Hosp Med Ctr, Div Endocrinol, Cincinnati, OH 45229 - USA

^[8] I, Cincinnati Childrens Hosp Med Ctr, Ctr Chronobiol, Cincinnati, OH 45229 - USA

^[9] Univ Virginia, Sch Med, Dept Pediat, Div Pediat Gastroenterol Hepatol & Nutr, Charlottesville, VA 22908 - USA

• Tipo de documento: Artigo Científico
• Fonte: EMBO Journal; v. 41, n. 2 OCT 2021.
• Citações Web of Science: 1

Resumo

Circadian rhythms regulate diverse aspects of gastrointestinal physiology ranging from the composition of microbiota to motility. However, development of the intestinal circadian clock and detailed mechanisms regulating circadian physiology of the intestine remain largely unknown. In this report, we show that both pluripotent stem cell-derived human intestinal organoids engrafted into mice and patient-derived human intestinal enteroids possess 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 to TcdB. RNA-Seq analysis shows that similar to 3-10% of the detectable transcripts are rhythmically expressed in mouse and human enteroids. Remarkably, we observe anti-phasic gene expression of Rac1, a small GTPase directly inactivated by TcdB, between mouse and human enteroids, and disruption of Rac1 abolishes clock-dependent necrotic cell death responses. Our findings uncover robust functions of circadian rhythms regulating clock-controlled genes in both mouse and human enteroids governing organism-specific, circadian phase-dependent necrotic cell death responses, and lay a foundation for human organ- and disease-specific investigation of clock functions using human organoids for translational applications. (AU)

• Processo FAPESP: 19/04451-3 - Papel do TSC22D3, um fator de transcrição de zíper de leucina induzido por glicocorticóide, no relógio molecular circadiano
• Beneficiário: Danilo Eugênio de França Laurindo Flôres
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado
• Processo FAPESP: 17/16242-4 - Estudo computacional do fotoperiodismo na sincronização fótica e alimentar em sistemas circadianos multioscilatórios
• Beneficiário: Danilo Eugênio de França Laurindo Flôres
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado