The microbiota programs DNA methylation to control intestinal homeostasis and inflammation

Ihab Ansari; Günter Raddatz; Julian Gutekunst; Meshi Ridnik; Daphne Cohen; Monther Abu-Remaileh; Timur Tuganbaev; Hagit Shapiro; Eli Pikarsky; Eran Elinav; Frank Lyko; Yehudit Bergman

doi:10.1038/s41564-019-0659-3

The microbiota programs DNA methylation to control intestinal homeostasis and inflammation

Ihab Ansari, Günter Raddatz, Julian Gutekunst, Meshi Ridnik, Daphne Cohen, Monther Abu-Remaileh, Timur Tuganbaev, Hagit Shapiro, Eli Pikarsky, Eran Elinav, Frank Lyko, Yehudit Bergman^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

82 Scopus citations

Abstract

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.

Original language	American English
Pages (from-to)	610-619
Number of pages	10
Journal	Nature Microbiology
Volume	5
Issue number	4
DOIs	https://doi.org/10.1038/s41564-019-0659-3
State	Published - 1 Apr 2020

Bibliographical note

Funding Information:
We thank all members of our groups for helpful discussions. This work was supported by research grants from the Israel Academy of Sciences (grant 734/13 Y.B.), the Israel Cancer Research Foundation (grant 211410 to Y.B.), The Emanuel Rubin Chair in Medical Sciences (Y.B.), the Israel Center of Excellence Program (grant 1796/12 to Y.B.), the Helmholtz-Israel-Cooperation in Personalized Medicine (to Y.B. and F.L.), the Helmholtz program ‘Aging and Metabolic Programming’ (AMPro, to F.L.) and the German-Israeli Foundation (grant 1424 to Y.B. and F.L.).

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41564-019-0659-3

Cite this

@article{599ec804a3f64c588b97d918aefec511,

title = "The microbiota programs DNA methylation to control intestinal homeostasis and inflammation",

abstract = "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 {\textquoteleft}early sentinel{\textquoteright} 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.",

author = "Ihab Ansari and G{\"u}nter Raddatz and Julian Gutekunst and Meshi Ridnik and Daphne Cohen and Monther Abu-Remaileh and Timur Tuganbaev and Hagit Shapiro and Eli Pikarsky and Eran Elinav and Frank Lyko and Yehudit Bergman",

note = "Funding Information: We thank all members of our groups for helpful discussions. This work was supported by research grants from the Israel Academy of Sciences (grant 734/13 Y.B.), the Israel Cancer Research Foundation (grant 211410 to Y.B.), The Emanuel Rubin Chair in Medical Sciences (Y.B.), the Israel Center of Excellence Program (grant 1796/12 to Y.B.), the Helmholtz-Israel-Cooperation in Personalized Medicine (to Y.B. and F.L.), the Helmholtz program {\textquoteleft}Aging and Metabolic Programming{\textquoteright} (AMPro, to F.L.) and the German-Israeli Foundation (grant 1424 to Y.B. and F.L.). Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2020",

month = apr,

day = "1",

doi = "10.1038/s41564-019-0659-3",

language = "American English",

volume = "5",

pages = "610--619",

journal = "Nature Microbiology",

issn = "2058-5276",

publisher = "Nature Publishing Group",

number = "4",

}

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 - Funding Information: We thank all members of our groups for helpful discussions. This work was supported by research grants from the Israel Academy of Sciences (grant 734/13 Y.B.), the Israel Cancer Research Foundation (grant 211410 to Y.B.), The Emanuel Rubin Chair in Medical Sciences (Y.B.), the Israel Center of Excellence Program (grant 1796/12 to Y.B.), the Helmholtz-Israel-Cooperation in Personalized Medicine (to Y.B. and F.L.), the Helmholtz program ‘Aging and Metabolic Programming’ (AMPro, to F.L.) and the German-Israeli Foundation (grant 1424 to Y.B. and F.L.). 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

M3 - Article

C2 - 32015497

AN - SCOPUS:85078877003

SN - 2058-5276

VL - 5

SP - 610

EP - 619

JO - Nature Microbiology

JF - Nature Microbiology

IS - 4

ER -

The microbiota programs DNA methylation to control intestinal homeostasis and inflammation

Abstract

Bibliographical note

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this