Ontogeny and function of the circadian clock in intestinal organoids.
Rac1
Clostridium difficile toxin B
circadian rhythms
human enteroids
intestinal organoids
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
17 12 2022
17 12 2022
Historique:
revised:
30
09
2021
received:
06
10
2020
accepted:
11
10
2021
pubmed:
28
10
2021
medline:
17
2
2022
entrez:
27
10
2021
Statut:
ppublish
Résumé
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 ~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.
Identifiants
pubmed: 34704277
doi: 10.15252/embj.2020106973
pmc: PMC8762567
doi:
Substances chimiques
Bacterial Proteins
0
Bacterial Toxins
0
RAC1 protein, human
0
toxB protein, Clostridium difficile
0
rac1 GTP-Binding Protein
EC 3.6.5.2
Banques de données
GEO
['GSE179028']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e106973Subventions
Organisme : NIDDK NIH HHS
ID : UG3 DK119982
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK078392
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK118904
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI116497
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI116491
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS054794
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK117005
Pays : United States
Organisme : NICHD NIH HHS
ID : P01 HD093363
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021 The Authors Published under the terms of the CC BY NC ND 4.0 license.
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