Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis

Theresa Alenghat; Lisa C Osborne; Steven A Saenz; Dmytro Kobuley; Carly G K Ziegler; Shannon E Mullican; Inchan Choi; Stephanie Grunberg; Rohini Sinha; Meghan Wynosky-Dolfi; Annelise Snyder; Paul R Giacomin; Karen L Joyce; Tram B Hoang; Meenakshi Bewtra; Igor E Brodsky; Gregory F Sonnenberg; Frederic D Bushman; Kyoung-Jae Won; Mitchell A Lazar; David Artis

doi:10.1038/nature12687

Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis

Theresa Alenghat, Lisa C Osborne, Steven A Saenz, Dmytro Kobuley, Carly G K Ziegler, Shannon E Mullican, Inchan Choi, Stephanie Grunberg, Rohini Sinha, Meghan Wynosky-Dolfi, Annelise Snyder, Paul R Giacomin, Karen L Joyce, Tram B Hoang, Meenakshi Bewtra, Igor E Brodsky, Gregory F Sonnenberg, Frederic D Bushman, Kyoung-Jae Won, Mitchell A LazarDavid Artis

130 Citationer (Scopus)

Abstract

The development and severity of inflammatory bowel diseases and other chronic inflammatory conditions can be influenced by host genetic and environmental factors, including signals derived from commensal bacteria. However, the mechanisms that integrate these diverse cues remain undefined. Here we demonstrate that mice with an intestinal epithelial cell (IEC)-specific deletion of the epigenome-modifying enzyme histone deacetylase 3 (HDAC3(ΔIEC) mice) exhibited extensive dysregulation of IEC-intrinsic gene expression, including decreased basal expression of genes associated with antimicrobial defence. Critically, conventionally housed HDAC3(ΔIEC) mice demonstrated loss of Paneth cells, impaired IEC function and alterations in the composition of intestinal commensal bacteria. In addition, HDAC3(ΔIEC) mice showed significantly increased susceptibility to intestinal damage and inflammation, indicating that epithelial expression of HDAC3 has a central role in maintaining intestinal homeostasis. Re-derivation of HDAC3(ΔIEC) mice into germ-free conditions revealed that dysregulated IEC gene expression, Paneth cell homeostasis and intestinal barrier function were largely restored in the absence of commensal bacteria. Although the specific mechanisms through which IEC-intrinsic HDAC3 expression regulates these complex phenotypes remain to be determined, these data indicate that HDAC3 is a critical factor that integrates commensal-bacteria-derived signals to calibrate epithelial cell responses required to establish normal host-commensal relationships and maintain intestinal homeostasis.

Originalsprog	Engelsk
Tidsskrift	Nature
Vol/bind	504
Udgave nummer	7478
Sider (fra-til)	153-7
Antal sider	5
ISSN	0028-0836
DOI	https://doi.org/10.1038/nature12687
Status	Udgivet - 5 dec. 2013
Udgivet eksternt	Ja

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10.1038/nature12687

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Alenghat, T., Osborne, L. C., Saenz, S. A., Kobuley, D., Ziegler, C. G. K., Mullican, S. E., Choi, I., Grunberg, S., Sinha, R., Wynosky-Dolfi, M., Snyder, A., Giacomin, P. R., Joyce, K. L., Hoang, T. B., Bewtra, M., Brodsky, I. E., Sonnenberg, G. F., Bushman, F. D., Won, K.-J., ... Artis, D. (2013). Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis. Nature, 504(7478), 153-7. https://doi.org/10.1038/nature12687

Alenghat, T, Osborne, LC, Saenz, SA, Kobuley, D, Ziegler, CGK, Mullican, SE, Choi, I, Grunberg, S, Sinha, R, Wynosky-Dolfi, M, Snyder, A, Giacomin, PR, Joyce, KL, Hoang, TB, Bewtra, M, Brodsky, IE, Sonnenberg, GF, Bushman, FD, Won, K-J, Lazar, MA & Artis, D 2013, 'Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis', Nature, bind 504, nr. 7478, s. 153-7. https://doi.org/10.1038/nature12687

@article{39b07bbcfc324e6d997b7203121c9871,

title = "Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis",

abstract = "The development and severity of inflammatory bowel diseases and other chronic inflammatory conditions can be influenced by host genetic and environmental factors, including signals derived from commensal bacteria. However, the mechanisms that integrate these diverse cues remain undefined. Here we demonstrate that mice with an intestinal epithelial cell (IEC)-specific deletion of the epigenome-modifying enzyme histone deacetylase 3 (HDAC3(ΔIEC) mice) exhibited extensive dysregulation of IEC-intrinsic gene expression, including decreased basal expression of genes associated with antimicrobial defence. Critically, conventionally housed HDAC3(ΔIEC) mice demonstrated loss of Paneth cells, impaired IEC function and alterations in the composition of intestinal commensal bacteria. In addition, HDAC3(ΔIEC) mice showed significantly increased susceptibility to intestinal damage and inflammation, indicating that epithelial expression of HDAC3 has a central role in maintaining intestinal homeostasis. Re-derivation of HDAC3(ΔIEC) mice into germ-free conditions revealed that dysregulated IEC gene expression, Paneth cell homeostasis and intestinal barrier function were largely restored in the absence of commensal bacteria. Although the specific mechanisms through which IEC-intrinsic HDAC3 expression regulates these complex phenotypes remain to be determined, these data indicate that HDAC3 is a critical factor that integrates commensal-bacteria-derived signals to calibrate epithelial cell responses required to establish normal host-commensal relationships and maintain intestinal homeostasis. ",

keywords = "Adult, Animals, Bacteria/genetics, Colitis, Ulcerative/enzymology, Crohn Disease/enzymology, Female, Gene Deletion, Gene Expression Profiling, Gene Expression Regulation, Histone Deacetylases/genetics, Homeostasis, Humans, Intestinal Mucosa/enzymology, Intestines/microbiology, Male, Mice, Mice, Inbred C57BL, Paneth Cells/cytology, RNA, Ribosomal, 16S/genetics, Signal Transduction, Symbiosis",

author = "Theresa Alenghat and Osborne, {Lisa C} and Saenz, {Steven A} and Dmytro Kobuley and Ziegler, {Carly G K} and Mullican, {Shannon E} and Inchan Choi and Stephanie Grunberg and Rohini Sinha and Meghan Wynosky-Dolfi and Annelise Snyder and Giacomin, {Paul R} and Joyce, {Karen L} and Hoang, {Tram B} and Meenakshi Bewtra and Brodsky, {Igor E} and Sonnenberg, {Gregory F} and Bushman, {Frederic D} and Kyoung-Jae Won and Lazar, {Mitchell A} and David Artis",

year = "2013",

month = dec,

day = "5",

doi = "10.1038/nature12687",

language = "English",

volume = "504",

pages = "153--7",

journal = "Nature",

issn = "0028-0836",

publisher = "nature publishing group",

number = "7478",

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TY - JOUR

T1 - Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis

AU - Alenghat, Theresa

AU - Osborne, Lisa C

AU - Saenz, Steven A

AU - Kobuley, Dmytro

AU - Ziegler, Carly G K

AU - Mullican, Shannon E

AU - Choi, Inchan

AU - Grunberg, Stephanie

AU - Sinha, Rohini

AU - Wynosky-Dolfi, Meghan

AU - Snyder, Annelise

AU - Giacomin, Paul R

AU - Joyce, Karen L

AU - Hoang, Tram B

AU - Bewtra, Meenakshi

AU - Brodsky, Igor E

AU - Sonnenberg, Gregory F

AU - Bushman, Frederic D

AU - Won, Kyoung-Jae

AU - Lazar, Mitchell A

AU - Artis, David

PY - 2013/12/5

Y1 - 2013/12/5

N2 - The development and severity of inflammatory bowel diseases and other chronic inflammatory conditions can be influenced by host genetic and environmental factors, including signals derived from commensal bacteria. However, the mechanisms that integrate these diverse cues remain undefined. Here we demonstrate that mice with an intestinal epithelial cell (IEC)-specific deletion of the epigenome-modifying enzyme histone deacetylase 3 (HDAC3(ΔIEC) mice) exhibited extensive dysregulation of IEC-intrinsic gene expression, including decreased basal expression of genes associated with antimicrobial defence. Critically, conventionally housed HDAC3(ΔIEC) mice demonstrated loss of Paneth cells, impaired IEC function and alterations in the composition of intestinal commensal bacteria. In addition, HDAC3(ΔIEC) mice showed significantly increased susceptibility to intestinal damage and inflammation, indicating that epithelial expression of HDAC3 has a central role in maintaining intestinal homeostasis. Re-derivation of HDAC3(ΔIEC) mice into germ-free conditions revealed that dysregulated IEC gene expression, Paneth cell homeostasis and intestinal barrier function were largely restored in the absence of commensal bacteria. Although the specific mechanisms through which IEC-intrinsic HDAC3 expression regulates these complex phenotypes remain to be determined, these data indicate that HDAC3 is a critical factor that integrates commensal-bacteria-derived signals to calibrate epithelial cell responses required to establish normal host-commensal relationships and maintain intestinal homeostasis.

AB - The development and severity of inflammatory bowel diseases and other chronic inflammatory conditions can be influenced by host genetic and environmental factors, including signals derived from commensal bacteria. However, the mechanisms that integrate these diverse cues remain undefined. Here we demonstrate that mice with an intestinal epithelial cell (IEC)-specific deletion of the epigenome-modifying enzyme histone deacetylase 3 (HDAC3(ΔIEC) mice) exhibited extensive dysregulation of IEC-intrinsic gene expression, including decreased basal expression of genes associated with antimicrobial defence. Critically, conventionally housed HDAC3(ΔIEC) mice demonstrated loss of Paneth cells, impaired IEC function and alterations in the composition of intestinal commensal bacteria. In addition, HDAC3(ΔIEC) mice showed significantly increased susceptibility to intestinal damage and inflammation, indicating that epithelial expression of HDAC3 has a central role in maintaining intestinal homeostasis. Re-derivation of HDAC3(ΔIEC) mice into germ-free conditions revealed that dysregulated IEC gene expression, Paneth cell homeostasis and intestinal barrier function were largely restored in the absence of commensal bacteria. Although the specific mechanisms through which IEC-intrinsic HDAC3 expression regulates these complex phenotypes remain to be determined, these data indicate that HDAC3 is a critical factor that integrates commensal-bacteria-derived signals to calibrate epithelial cell responses required to establish normal host-commensal relationships and maintain intestinal homeostasis.

KW - Adult

KW - Animals

KW - Bacteria/genetics

KW - Colitis, Ulcerative/enzymology

KW - Crohn Disease/enzymology

KW - Female

KW - Gene Deletion

KW - Gene Expression Profiling

KW - Gene Expression Regulation

KW - Histone Deacetylases/genetics

KW - Homeostasis

KW - Humans

KW - Intestinal Mucosa/enzymology

KW - Intestines/microbiology

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Paneth Cells/cytology

KW - RNA, Ribosomal, 16S/genetics

KW - Signal Transduction

KW - Symbiosis

U2 - 10.1038/nature12687

DO - 10.1038/nature12687

M3 - Journal article

C2 - 24185009

SN - 0028-0836

VL - 504

SP - 153

EP - 157

JO - Nature

JF - Nature

IS - 7478

ER -

Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis

Abstract

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