For COVID-19 vaccine updates, please review our information guide. For patient eligibility and scheduling availability, please visit VaccineTogetherNY.org.

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

TitleHistone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis.
Publication TypeJournal Article
Year of Publication2013
AuthorsAlenghat 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
JournalNature
Volume504
Issue7478
Pagination153-7
Date Published2013 Dec 5
ISSN1476-4687
KeywordsAdult, Animals, Bacteria, Colitis, Ulcerative, Crohn Disease, Female, Gene Deletion, Gene Expression Profiling, Gene Expression Regulation, Histone Deacetylases, Homeostasis, Humans, Intestinal Mucosa, Intestines, Male, Mice, Mice, Inbred C57BL, Paneth Cells, RNA, Ribosomal, 16S, Signal Transduction, Symbiosis
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.

DOI10.1038/nature12687
Alternate JournalNature
PubMed ID24185009
PubMed Central IDPMC3949438
Grant List2-P30 CA016520 / CA / NCI NIH HHS / United States
AI061570 / AI / NIAID NIH HHS / United States
AI074878 / AI / NIAID NIH HHS / United States
AI087990 / AI / NIAID NIH HHS / United States
AI095466 / AI / NIAID NIH HHS / United States
AI095608 / AI / NIAID NIH HHS / United States
AI097333 / AI / NIAID NIH HHS / United States
AI102942 / AI / NIAID NIH HHS / United States
AI106697 / AI / NIAID NIH HHS / United States
DK043806 / DK / NIDDK NIH HHS / United States
DP5 OD012116 / OD / NIH HHS / United States
DP5OD012116 / OD / NIH HHS / United States
F31-GM082187 / GM / NIGMS NIH HHS / United States
K08 DK084347 / DK / NIDDK NIH HHS / United States
K08 DK093784 / DK / NIDDK NIH HHS / United States
K08-DK084347 / DK / NIDDK NIH HHS / United States
K08-DK093784 / DK / NIDDK NIH HHS / United States
P01 AI106697 / AI / NIAID NIH HHS / United States
P30 CA016520 / CA / NCI NIH HHS / United States
P30 DK019525 / DK / NIDDK NIH HHS / United States
P30-DK050306 / DK / NIDDK NIH HHS / United States
P30-DK19525 / DK / NIDDK NIH HHS / United States
R01 AI061570 / AI / NIAID NIH HHS / United States
R01 AI074878 / AI / NIAID NIH HHS / United States
R01 AI095466 / AI / NIAID NIH HHS / United States
R01 AI097333 / AI / NIAID NIH HHS / United States
R01 AI102942 / AI / NIAID NIH HHS / United States
R21 AI083480 / AI / NIAID NIH HHS / United States
R21 AI087990 / AI / NIAID NIH HHS / United States
R21 AI105346 / AI / NIAID NIH HHS / United States
R21-AI105346 / AI / NIAID NIH HHS / United States
R37 DK043806 / DK / NIDDK NIH HHS / United States
T32-RR007063 / RR / NCRR NIH HHS / United States
U01 AI095608 / AI / NIAID NIH HHS / United States

Weill Cornell Medicine Microbiology and Immunology 1300 York Avenue, Box 62 New York, NY 10065 Phone: (212) 746-6505 Fax: (212) 746-8587