TY - JOUR
T1 - The microbiota programs DNA methylation to control intestinal homeostasis and inflammation
AU - Ansari, Ihab
AU - Raddatz, Günter
AU - Gutekunst, Julian
AU - Ridnik, Meshi
AU - Cohen, Daphne
AU - Abu-Remaileh, Monther
AU - Tuganbaev, Timur
AU - Shapiro, Hagit
AU - Pikarsky, Eli
AU - Elinav, Eran
AU - Lyko, Frank
AU - Bergman, Yehudit
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/4/1
Y1 - 2020/4/1
N2 - Although much research has been done on the diversity of the gut microbiome, little is known about how it influences intestinal homeostasis under normal and pathogenic conditions. Epigenetic mechanisms have recently been suggested to operate at the interface between the microbiota and the intestinal epithelium. We performed whole-genome bisulfite sequencing on conventionally raised and germ-free mice, and discovered that exposure to commensal microbiota induced localized DNA methylation changes at regulatory elements, which are TET2/3-dependent. This culminated in the activation of a set of ‘early sentinel’ response genes to maintain intestinal homeostasis. Furthermore, we demonstrated that exposure to the microbiota in dextran sodium sulfate-induced acute inflammation results in profound DNA methylation and chromatin accessibility changes at regulatory elements, leading to alterations in gene expression programs enriched in colitis- and colon-cancer-associated functions. Finally, by employing genetic interventions, we show that microbiota-induced epigenetic programming is necessary for proper intestinal homeostasis in vivo.
AB - Although much research has been done on the diversity of the gut microbiome, little is known about how it influences intestinal homeostasis under normal and pathogenic conditions. Epigenetic mechanisms have recently been suggested to operate at the interface between the microbiota and the intestinal epithelium. We performed whole-genome bisulfite sequencing on conventionally raised and germ-free mice, and discovered that exposure to commensal microbiota induced localized DNA methylation changes at regulatory elements, which are TET2/3-dependent. This culminated in the activation of a set of ‘early sentinel’ response genes to maintain intestinal homeostasis. Furthermore, we demonstrated that exposure to the microbiota in dextran sodium sulfate-induced acute inflammation results in profound DNA methylation and chromatin accessibility changes at regulatory elements, leading to alterations in gene expression programs enriched in colitis- and colon-cancer-associated functions. Finally, by employing genetic interventions, we show that microbiota-induced epigenetic programming is necessary for proper intestinal homeostasis in vivo.
UR - http://www.scopus.com/inward/record.url?scp=85078877003&partnerID=8YFLogxK
U2 - 10.1038/s41564-019-0659-3
DO - 10.1038/s41564-019-0659-3
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C2 - 32015497
AN - SCOPUS:85078877003
SN - 2058-5276
VL - 5
SP - 610
EP - 619
JO - Nature Microbiology
JF - Nature Microbiology
IS - 4
ER -